SURVEY OF OPHTHALMOLOGY VOLUME 49 • NUMBER 2 • MARCH–APRIL 2004

MAJOR REVIEW

Ocular Genetics: Current Understanding

Ian M. MacDonald, MSc, MD CM,1 Mai Tran, BSc,1 and Maria A. Musarella, MD2,3

1
Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada; 2Long Island College Hospital,
Department of Ophthalmology, Brooklyn, New York, USA; and 3SUNY Downstate Medical Center of Brooklyn,
Department of Ophthalmology, Brooklyn, New York, USA

Abstract. Over the past decade, there has been an exponential increase in our knowledge of heritable
eye conditions. Coincidentally, our ability to provide accurate genetic diagnoses has allowed
appropriate counseling to patients and families. A summary of our current understanding of ocular
genetics will prove useful to clinicians, researchers, and students as an introduction to the subject.
(Surv Ophthalmol 49:159–196, 2004. 쑖 2004 Elsevier Inc. All rights reserved.)

Key words. genetic counseling • molecular genetics • ocular genetics

I. Introduction will need to emerge in the future to study the effect

More than 10 years have passed since the Survey of
Ophthalmology last reviewed ocular genetics.288 The
pace of gene discovery has since increased signifi-
cantly as we now use technologies and the Human
Genome Project databases which were not previously
available. The contribution of ocular genetics to
human discovery has been exceptional, beginning
with a strong interest in ocular genetics by many
clinical ophthalmologists who carefully described
the patterns of inheritance of familial eye disorders.
Families readily participated in research to under-
stand the nature of their illness with the hope that
new treatments might be found to prevent blindness.
A specific clinical and genetic diagnosis provides the
patient and family with a framework for discussions
on prognosis, treatment, and the heritability of a
condition. As genotyping of specific conditions is pos-
sible in research and clinical laboratories, we are
beginning to consider targeting specific therapies for
these conditions. Clinical trials for these conditions
of these treatments.
An up-to-date summary of the present state of
ocular genetics was deemed important. This review
has limited its scope to human conditions and syn-
dromes that primarily affect the eye with the intent
of being comprehensive but not exhaustive. Some
conditions, especially metabolic disorders affecting
the eye, have not been included; whereas some
multisystem disorders have been included to allow a
more complete discussion of ocular genetics. Al-
though the disorders are presented in the tradi-
tional manner according to their phenotype, we are
increasingly aware that mutations in the same gene
may result in disparate phenotypes.
The original strategies of gene discovery used link-
age analysis with molecular genetic tools to first
define the locus of a particular gene, as in the case
of X-linked retinitis pigmentosa.48 Physical mapping
then refined the map location of the gene to an area
from which a gene could be cloned. This approach

159
쑖 2004 by Elsevier Inc. 0039-6257/04/$–see front matter
All rights reserved. doi:10.1016/j.survophthal.2003.12.003
160 Surv Ophthalmol 49 (2) March–April 2004
has generally been defined as positional cloning. As the
resources of cloned segments and map locations
increased, an alternate approach, candidate gene analy-
sis, was used successfully in some cases. If the map
location was defined, a search of databases could
reveal a gene mapped to the same location that po-
tentially was involved in the pathophysiology of the
condition. Autosomal dominant RP (adRP) was
linked to the same locus as the gene for rhodopsin
(RHO), and mutations were subsequently discovered
in RHO in patients with adRP.106 Our knowledge of
other mammalian genomes has been additive in the
search for genes underlying human conditions. For
example, cloning the mouse pink-eye dilution gene,
p, enabled the discovery of the human homologue,
P, that is mutated in tyrosinase positive oculocuta-
neous albinism.140 Similary, cloning the brown (b)
gene in mouse allowed Boissy and coworkers to iden-
tify mutations in the TYRP-1 gene in brown oculocu-
taneous albinism.55
In the table of heritable eye conditions accompa-
nying this review (Table 1), we have listed the disor-
ders by their phenotype. Where possible, the gene
(or symbol used to denote the gene) which is mu-
tated, and the protein encoded by that gene have
been verified according to the nomenclature pro-
posed by the Human Gene Nomenclature Database.
The exceptional resources of Online Mendelian Inher-
itance in Man (OMIM) and the Retinal Information
Network (RetNet) will continue to provide up-
to-date knowledge of specific conditions. There is
currently no clearinghouse for clinicians who are
interested in pursuing the genetics of a heritable
condition in a patient or family. GeneTests does,
however, act as a resource to link clinicians with diag-
nostic and research laboratories for some of these
conditions.
II. Anterior Segment Conditions
A. ANIRIDIA
Aniridia is a rare disorder that causes corneal
pannus, cataracts, glaucoma, partial or complete ab-
sence of the iris, and foveal hypoplasia (Fig. 1).365
The degree of visual impairment is quite variable
and the phenotype of aniridia can include cases of
autosomal dominant keratitis.275 Differences in the
degree to which the anterior segment is affected by
pannus, iris hypoplasia, and cataracts can be observ-
ed between related affected individuals and within
individuals.241
Aniridia can be inherited as an autosomal domi-
nant trait or occur sporadically, without a previous
family history, presumably due to a new mutation or
non-paternity. One-third of sporadic cases of aniridia
develop Wilms tumor. A sporadic case of aniridia
MACDONALD ET AL
warrants investigation with abdominal ultrasound ex-
amination to rule out the possibility of Wilms
tumor.166 Riccardi and coworkers described several
cases of aniridia and Wilms tumor associated with an
interstitial 11p deletion and proposed a contiguous
gene syndrome (WAGR ⫽ Wilms tumor, aniridia,
genitourinary abnormalities, and mental retardation)
due to genes in the region.337 If a sporadic case of
aniridia exhibits multiple congenital anomalies (es-
pecially genitourinary anomalies), karyotypic analy-
sis is appropriate. The syndromic form of aniridia
(WAGR) results from deletion of the contiguous
genes: PAX6 and the Wilms tumor suppressor gene
1 (WT1).319
The gene for aniridia, PAX6, was cloned by Ton
et al.392 The PAX (paired box) genes were identified
and so designated because of sequence homology
to the Drosophila segmentation genes, paired and
gooseberry.68 To date nine members of this gene
family have been identified in humans and are desig-
nated PAX1 through PAX9.348 All cases of familial
aniridia result from a mutation in one copy of the
PAX6 gene creating haploinsufficiency of the gene
product.146 For patients with a clear history of domi-
nantly inherited aniridia, further investigations are
generally unnecessary.
B. AXENFELD-RIEGER MALFORMATION
Abnormal migration of neural crest cells and their
derivative structures are presumed to cause anoma-
lous formation of the anterior segment of the eye.34,187
During the sixth week of embryonic life, neural crest
cells migrate to form the corneal endothelium, the
iris stoma, and the trabecular meshwork.22,187 Differ-
entiation of neural crest cells and a cascade of tran-
scription factors are involved in normal anterior
segment morphogenesis. The pathogenesis of several
anterior segment disorders: iris hypoplasia or irido-
goniodysgenesis, posterior polymorphous corneal
dystrophy, and Axenfeld-Rieger malformation may
then be linked to defects in these genes.
Although traditional teaching has separated ante-
rior segment malformations into those limited to
the eye and those including systemic features, the
genetics of these disorders suggests that mutations
in a few genes may cause overlapping phenotypes.
The Axenfeld-Rieger malformation comprises Axen-
feld-Rieger anomaly (ARA) and Axenfeld-Rieger
syndrome (ARS). ARA has findings limited to the
eye, including a malformed anterior chamber and
prominent, anteriorly displaced Schwalbe’s line (Fig.
2).189 ARS has added systemic features including
dental anomalies, failure of involution of the perium-
bilical skin (umbilical hernia), mild craniofacial
dysmorphism, and, less frequently, hydrocephalus
OCULAR GENETICS: CURRENT UNDERSTANDING 161

TABLE 1
Heritable Eye Disorders
Gene/
Symbol Protein Locus References
Anterior Segment Conditions
Aniridia PAX6 Paired box 11p13 392
transcription
factor 6
Axenfeld-Rieger FOXC1 Forkhead box 6p25 266,307
anomaly C1 transcription
factor
Axenfeld-Rieger PITX2 Paired-like 4q25 360
syndrome homeodomain
transcription
factor 2
Axenfeld-Rieger RIEG2 13q14 325
syndrome
Axenfeld-Rieger 16q24
syndrome
Iridogoniodysgenesis FOXC1 Forkhead box 6p25 228,229
anomaly (iris C1 transcription
hypoplasia) factor
Iridogoniodysgenesis PITX2 Paired-like 4q25 12,226
syndrome homeodomain
transcription
factor 2
Peters anomaly PAX6 Paired box 11p13 159
transcription
factor 6
Peters anomaly PITX2 Paired-like 4q25 100
homeodomain
transcription
factor 2
Corneal Dystrophies
Avellino corneal βig-h3 Kerato- 5q31 285
dystrophy epithelin
Granular corneal βig-h3 Kerato-epithelin 5q31 285
dystrophy (Groenouw type I)
Lattice type I βig-h3 Kerato-epithelin 5q31 285
corneal dystrophy
Meesman dystrophy KRT3 Keratin 3 17q12 178
KRT12 Keratin 12
Reis-Bücklers βig-h3 Kerato-epithelin 5q31 285
corneal dystrophy
Lens disorders
Aculeiform CRYGD Crystallin, 2q33-q35 164
gamma D
Anterior Polar 14q24-qter 128,272
Type I (CTAA1)
Anterior Polar 17p13 44
Type II (CTAA2)
Posterior Polar 1pter-p36.1 177
Posterior Polar CRYAB Crystallin, 11q22-q22.3 43
alpha B
Cerulean 17q24 21
Type I (CCA1)
Cerulean CRYBB2 Crystallin, 22q11.2-12.2 221,233
Type II (CCA2) beta B2
Lamellar Zonular GJA8 Connexin 1q21.1 368
pulverulent (CZP1) 50
(Coppock)
Coppock-like (CCL) CRYBB2 Crystallin, 22q11.2-12.2 145
beta B2
(continued)
162 Surv Ophthalmol 49 (2) March–April 2004 MACDONALD ET AL

TABLE 1
Continued
Gene/
Symbol Protein Locus References
Coppock-like (CCL) CRYGC Crystallin, 2q33-q35 164,237
gamma C
Congenital cataract (ad) PITX3 Paired-like 10q25 361
homeodomain
transcription factor 3
Congenital cataract (ad) MIP Major 12cen-q14 130
intrinsic
protein
Congenital cataract (ar) CRYAA Crystallin, 21q22.3 329
alpha A
Marner type (CAM) 16q22.1 110
Volkmann type 1pter-1p36.13 109,172
Dominant pulverulent CRYBB1 Crystallin, 247
beta B1
Dominant zonular GJA3 Connexin 13q11-q12 335
pulverulent (CZP3) 46
Nonnuclear polymorphic 2q33-q35 344
congenital (ad)
Zonular with sutural CRYBA1 Crystallin, 17q11-q12 314
opacities (CCZS) beta A1
Glaucoma
Normal tension glaucoma OPTN Optineurin 10p13 336
Primary open MYOC Myocilin 1q21-23 38,384
angle, aggressive (GLC1A)
POAG (moderate 2cen-q13 381
tension) (GLC1B)
POAG (high tension) 3q21-q24 419
(GLC1C)
POAG (moderate 8q23 393
tension) (GLC1D)
POAG (normal 10p14-p15 351
tension) (GLC1E)
POAG (GLCIF) 7q35 420
Primary congenital CYP1B1 Cytochrome 2p21 350
(GLC3B) P450, subfamily,
polypeptide 1
Primary congenital 1p36 7
Pigment dispersion 7q35-q36 15
Pigment dispersion 18q11-q21 14
Vitreo-retinal Disorders
Erosive vitreo-retinopathy 5q13-q14 66
Familial FZD4 Frizzled 11q14-q21 343
exudative protein 4
vitreo-retinopathy, (ad)
Familial exudative NDP Norrin Xp11.3 42,78
vitreo-retinopathy, (x1)
Norrie disease NDP Norrin Xp11.3 42,78
Retinoschisis RS1 Retinoschisin Xp22.2 352
Wagner disease 5q14.3 66,322
Albinism
OCA Type IA TYR Tyrosinase 11q14-21 25
OCA Yellow – IB TYR Tyrosinase 11q14-21 25
OCA TYR Tyrosinase 11q14-21 25
Temperature-
sensitive – I-TS
OCA Type II P 15q11.2-q12 141,334
OCA Brown (Type III) B, TYRP-1 Tyrosinase-related 9p23 55
protein
(continued)
OCULAR GENETICS: CURRENT UNDERSTANDING 163

TABLE 1
Continued
Gene/
Symbol Protein Locus References
OCA Type IV Human Membrane- 5p 302
orthologue of associated
underwhite transport
protein
Ocular OA1 Novel protein Xp22.3 27
Color Vision Defects
Achromatopsia CNGB3 Cone cyclic 8q21-q22 387,418
(Pingelapese) nucleotide-gated
cation channel beta 3
Achromatopsia GNAT2 Cone specific 1p13 217
alpha subunit of
transducin
Incomplete CNGA3 Cyclic nucleotide gated 2q11.2 422
achromatopsia channel alpha 3
Rod CNGA3 Cyclic nucleotide 2q11.2 19,422
monochromacy gated channel
alpha 3
Rod 14 320
monochromacy
Blue cone BCM Xq28, multiple 230
monochromacy mutations and
deletions of
red/green cluster
Deuteranopia OPN1MW Green cone Xq28 298
pigment
Protanopia OPN1LW Red cone Xq28 298
pigment
Tritanopia OPN1SW Blue cone 7q31.3-q32 414
pigment
Autosomal Dominant Retinitis Pigmentosa
RP18 1q13-q23 427
RP4 RHO Rhodopsin 3q21-q24 104
RP7 RDS Peripherin 6p21.2-cen 105,194
Retinitis punctata albescens RDS Peripherin 6p21.1-cen 195
RP9 7p13-p15 176
RP10 IMPDH1 Inosine 7q31.3 60,277
mono-phosphate
dehydrogenase 1
RP1 ORP1 Oxygen- 8q11-q13 181
regulated
photoreceptor
protein 1
NRL Neural retina 14q11.2 46
leucine zipper
RP13 PRPF8 Pre-mRNA 17p13.3 149,262
processing
factor 8
RP17 17q22 4
FSCN2 Retinal fascin 17q25 401
RP11 PRPF31 Pre-mRNA 19q13.4 8,398
processing
factor 31
Autosomal Recessive Retinitis Pigmentosa
RP19 ABCA4 ATP binding 1p22 254
cassette
transporter
(continued)
164 Surv Ophthalmol 49 (2) March–April 2004 MACDONALD ET AL

TABLE 1
Continued
Gene/
Symbol Protein Locus References
RP12 (with para-arteriolar CRB1 Crumbs homolog 1 1q31-q32.1 95,96
preservation of RPE);
RP with Coat’s like
vasculopathy
RP28 2p11-p16 153
MERTK c-mer proto- 2q14.1 136
oncogene tyrosine
kinase
RP26 2q31-q33 32
Retinal degeneration PROML1 Prominin-like 1 4p 259
PDE6B Rod cGMP 4p16.3 31
phosphodiesterase,
beta
(rod) CNGA1 Cyclic nucleotide 4p12-cen 103
gated channel
alpha 1
Severe early onset LRAT Lecithin retinol 4q31.2 59
acyltransferase
RP29 4q32-q34 316
PDE6A Rod cGMP 5q31.1-q34 174
phosphodiesterase,
alpha
RP14 TULP1 Tubby-like 6p21.3 156
protein 1
RP25 6cen-q15 208
RGR Retinal G protein 10q23 76,281
coupled receptor
RPE degeneration RBP4 Retinol binding 10q24 359
protein 4
arRP including NR2E3 Nuclear receptor 15q23 142,157
Enhanced S-cone
syndrome
RP22 16p12.1-p12.3 123
Autosomal Recessive Retinal Degeneration
Bietti crystalline 4q35-tel 185
corneoretinopathy
Fundus albipunctatus RDH5 Retinol 12q13-q14 83,428
dehydrogenase 5
Retinitis punctata RLBP1 Retinaldehyde 15q26 69
albescens binding protein 1
X-linked Retinitis Pigmentosa
RP23 Xp22 161
RP6 Xp21.2 64
RP3, RP15 RPGR RP GTPase Xp21.1 265,289,290,397
regulator
RP2 Novel protein Xp11.3 48,160
RP24 Xq26-27 144
Digenic RP RDS/ROM1 Peripherin/rod 6p21.2;11q13 105
outer segment
protein-1
Choroideremia CHM Rab escort Xq21.1-q22.3 89
protein 1
Usher syndrome
USH1A (French) 14q32 199
USH1B MYO7A Myosin VIIA 11q13.5 410
USH1C Harmonin 11p15.1 416
USH1D CDH23 Cadherin related 10q21-q22 56,58,182,186
adhesion protein 23
(continued)
OCULAR GENETICS: CURRENT UNDERSTANDING 165

TABLE 1
Continued
Gene/
Symbol Protein Locus References
USH1E 21q21 75
USH1F PCDH15 Protocadherin 15 10q21-22 6
USH2A Usherin 1q41 416
USH2B 3p24.2-p23 167
USH2C 5q14-q21 326
USH3A Novel protein 3q21-q25 95,186
Leber Congenital Amaurosis
LCA1 GUCY2D Retinal guanylate 17p13.1 71
cyclase 2D
LCA2(RP20) RPE65 RPE-specific 1p31 154,236,281
protein
LCA3 14q24 379
LCA4 AIPL1 Aryl 17p13.1 374
hydrocarbon
receptor
interacting
protein-like 1
LCA5 6q11-q16 97
LCA6 RPGRIP1 RP GTPase 14q11 102
regulator
interacting
protein 1
CRB1 Crumbs 1q31 235
homolog 1
CRX ots-like photoreceptor- 19q13.3 388
expressed homeobox
transcription factor
Bardet-Beidl Syndrome
BBS1 11q13 33
BBS2 16q21 33
BBS3 3p13-p12 33,433
BBS4 15q22.3-q23 33
BBS5 2q31 426,431
BBS6 MKKS Putative chaperonin 20p12 201,383
Systemic Forms of RP
infantile Refsum PEX1 Peroxisome 7q21-q22 328
disease (ar) biogenesis
factor 1
Refsum disease (ar) PHYH Phytanolyl- 10p15.3-p12.2 183,271
CoA hydroxylase
Kearns-Sayre KSS ATPase subunit 6 Mitochondrial 280
Syndrome; chronic DNA, deletions
progressive
external
ophthalmoplegia
Neuropathy, ATPase subunit 6 Mitochondrial 169
ataxia and RP DNA, 8993
point mutation
RP with progressive MTTS2 tRNA serine 2 Mitochondrial 251
sensorineual hearing loss DNA, 12258
point mutation
RP and ataxia TTPA Alpha- 8q13-q13.3 429
tocopherol
transfer
protein
Congenital Stationary Night Blindness
ad GNAT1 Rod transducin, 3p21 104
alpha subunit
(continued)
166 Surv Ophthalmol 49 (2) March–April 2004 MACDONALD ET AL

TABLE 1
Continued
Gene/
Symbol Protein Locus References
ad PDE6B Rod cGMP 4p16.3 137
phosphodiesterase,
beta
Oguchi disease (ar) SAG Arrestin (S-antigen) 2q37.1 135
Oguchi disease RHOK Rhodopsin kinase 13q34 83
(ar)
CSNB1 (xl) NYX Nyctalopin Xp11.4-p11.3 36
CSNB2 (xl) CACNA1F L-type voltage-gated Xp11.23 37
calcium channel,
alpha 1F subunit
Macular Dystrophy
Best vitelliform dystrophy VMD2 Bestrophin 11q13 324,386
Doyne honeycomb EFEMP1 EGF-containing 2p16 385
retinal dystrophy fibulin-like
extracellular
matrix protein 1
Macular dystrophy; RDS Peripherin 6p21.2 121,218
pseudovitelliform
North Carolina MCDR1 6q14-q16.2 373
macular dystrophy
Sorsby fundus TIMP3 Tissue inhibitor 22q12.2-q13.2 18
dystrophy of
metalloproteinase
3
Stargardt ABCA4 ATP binding 1p22 10
macular dystrophy cassette
(ar) (STGD1) transporter
Stargardt-like ELOVL4 Elongation of 6q14 434
macular dystrophy (ad) very long chain
(STGD3) fatty acids 4
STGD4 (ad) 4p 215
Retinoblastoma
RB1 Tumor 13q14.2 74
suppressor
Gyrate Atrophy
OAT Ornithine 10q26 393,394
aminotransferase
Cone Dystrophy
COD1 (xl) Xp11.4 362
COD2 (xl) Xq27 41
COD3 (ad) GUCA1A Guanylate 6p21.1 317
cyclase
activator-1A
Cone Rod (CORD) Dystrophies
CORD1 18q21.1-q21.3 406
CORD2 CRX ots-like 19q13.3 132
photoreceptor-
expessed
homeobox
transcription
factor
CORD3 ABCA4 ATP binding 1p22 88
cassette
transporter
CORD5 17p13-p12 23
CORD6 GUCY2D Retinal 17p13.1 202,204
guanylate
cyclase 2D
(continued)
OCULAR GENETICS: CURRENT UNDERSTANDING 167

TABLE 1
Continued
Gene/
Symbol Protein Locus References
CORD7 6cen-q14 203
Optic Nerve
Optic atrophy (Kjer) OPA1 Mitochondrial 3q28-q29 10,93,108
dynamin-related protein
Dominant optic atrophy 18q13.2-q12.3 206
Optic nerve colobomas PAX2 Paired box 10q25 13,118
(oculorenal syndrome) protein 2
Leber hereditary LHON Complex, I, III, Mitochondrial 175
optic neuropathy IV of respiratory chain DNA, several
point mutations
Disorders of the Lids and Ocular Adnexae
Blepharophimosis, FOXL2 Forkhead box L2 3q23 90
ptosis, epicanthus transcription factor
inversus with
premature ovarian
failure (BPES type I)
BPES without ovarian FOXL2 Forkhead box L2 3q23 90
failure (BPES type II) transcription factor
Ptosis (ad) 1p32-p34.1 113
Ptosis (xl) Xq24-q27.1 264
Anophthalmia/Micro-ophthalmia
Anophthalmia Xq27-q28 151
Micro-ophthalmia (ad) 15q12-q15 283
Micro-ophthalmia (ar) 14q32 45
Nanophthalmia 11p 313
(microphthalmia) (ad)
Disorders of Ocular Motility
Congenital fibrosis of 12p12.1-q13.2 112
extraocular muscles,
type 1 (FEOM1)
FEOM2 (ar) ARIX Homeodomain 11q13.2 295
(PHOX2A) transcription
factor
FEOM3 16q24.2-q24.3 99,248
Congenital 2p13 47
oculomotor apraxia
Duane’s retraction 8q13 70
syndrome Type 1 (DURS1)
DURS2 2q31 17,116
Nystagmus, congenital Xq26-q27 207
motor 1 (NYS1)(xl)
NYS2 (ad) NYS2 6p12 205
Refractive Errors
Myopia 3 12q21-q23 432
(MYP3)(ad)
MYP2 (ad) 18p11.31 430
MYP1 (xl) Xq28 356
ad ⫽ autosomal dominant; ar ⫽ autosomal recessive; xl ⫽ X-linked.

and hearing, cardiac, kidney, and limb de-
fects.81,119,126,249 Both ARA and ARS behave as autoso-
mal dominantly inherited traits. Fifty percent of
individuals with AR malformation develop glaucoma
usually in childhood or young adulthood.367
Linkage analysis of families with ARA localized a
locus to chromosome 6p25.150 Mutations in the fork-
head-like 7 gene, FOXC1 which mapped to 6p25,
were independently identified in families with ARA
by Mears et al266 and Nishimura et al.307 Not surpris-
ingly, a mutation in this gene was later found in
ARS.273 Further, duplications of this gene have
been found in iris hypoplasia with glaucoma (irido-
goniodysgenesis)229 and in the AR malformation.306
Murray and coworkers first established linkage of
a locus for ARS (RIEG1) to chromosome 4q25.286
Later characterization of the RIEG1 gene identified
it as the homeobox transcription factor, PITX2.360
168 Surv Ophthalmol 49 (2) March–April 2004
Members of the homeobox transcription gene family
have roles in genetic control of development, espe-
cially in the specification of the body plan, pattern
formation, and determination of cell fate.222 The
spectrum of phenotypes iris hypoplasia, iridogonio-
dysgenesis syndrome (IDGS), and ARS is likely due
to the amount of residual PITX2 activity in patients
with mutations in this gene.220 Phillips et al localized
a second ARS locus, RIEG2, to chromosome 13q14
through linkage studies.325 A third putative locus at
16q24 for AR malformation has been inferred
through the studies of cases with chromosomal
anomalies.122,415
Iridogoniodysgenesis or iris hypoplasia is part of
the spectrum of Axenfeld-Reiger malformation. Iri-
dogoniodysgenesis (IGD) was first described by Berg
in 1932,40 as maldevelopment of the trabecular mesh-
work and iris. The pigmented iris epithelium is seen
through a hypoplastic anterior iris stroma resulting
in a peculiar eye color (slate gray or chocolate
brown). The normal pupillary sphincter stands out
as an elevated tan-colored ring against a rather fea-
tureless gray background (Fig. 3). Prominence of the
pupillary sphincter may also be seen in the Axenfeld-
Rieger malformation. Similar to the Axenfeld-Rieger
malformation, two phenotypes have been described:
IGD anomaly (IGDA) characterized by iris hypopla-
sia, goniodysgenesis, and juvenile glaucoma with no
systemic findings; and IGD syndrome (IGDS) with
additional nonocular features: dental and jaw anoma-
lies. Both traits are inherited in an autosomal domi-
nant fashion. Although phenotypic expression is
variable, penetrance of the trait is high.184,318,407 The
degree of iris and trabecular meshwork malforma-
tion does not correlate with either the development
or the severity of glaucoma.318,407 Glaucoma arises
in between 75% and 100% of patients with
IGD,150,274,286,407 and is usually detected in the second
decade of life.184
Iridogoniodysgenesis anomaly was originally
mapped to chromosome 6p25 by Mears and col-
leagues.267 Duplication of FOXC1, which maps to
6p25, has been shown in families with iris hypoplasia
(IGDA).228,229 IGDS was mapped to chromosome
4q25, allelic to ARS, and was later shown to be due to
mutations in PITX2.11,226 The major genes involved
in the AR malformation are therefore FOXC1 and
PITX2. Mutations in these genes cause a spectrum
of anterior segment phenotypes but within individual
families the phenotypes tend to be specific.
C. PETERS ANOMALY
Peters anomaly is a congenital malformation of
the anterior chamber of the eye resulting in corneal
clouding and variable iridolenticular corneal adhe-
sions.323,382 Cases are usually sporadic in nature, but
MACDONALD ET AL
families have been described in whom the disorder
is inherited as an autosomal dominant165,168 or au-
tosomal recessive trait.53 Mutations in PAX6 were
first implicated in Peters anomaly by Holmstrom and
colleagues.168 In 1994, Hanson et al reported that a
deletion of one copy of PAX6 caused Peters anom-
aly.159 A mutation in PITX2 has also been demon-
strated in a case of Peters anomaly.100 The patient’s
father, although not available for examination, was
reported to have nystagmus, glaucoma, and poor
dentition.
Other loci may also be involved in Peters anomaly
as the disorder occurs occasionally with systemic fea-
tures (Peters plus syndrome or Krause-Kivlin syn-
drome), hinting at the possibility of a contiguous
gene syndrome or mutations in a single gene with
phenotypic variability.163,210,211 Similar to cases of an-
iridia, Peters anomaly has been described in conjunc-
tion with Wilms tumor.111,190 A renal ultrasound
examination should be performed to rule out the
presence of Wilms tumor. At least five chromosomal
syndromes have been associated with Peters anomaly:
deletions in chromosomes 4,260 11,30 and 18,147 ring
chomosome 21,82 and a balanced translocation,
t(2;15).211
III. Corneal Dystrophies
A. big-h3
Skonier et al first isolated βig-h3, the human trans-
forming growth factor beta-induced gene.371,372
This gene maps to chromosome 5q31 and is tran-
scribed almost exclusively in the corneal epithelium
and stromal keratocytes.114 Using a candidate gene
approach, Munier et al found that mutations in this
gene cause four corneal disorders that map to 5q31:
granular corneal dystrophy or Groenouw type I, Reis-
Bücklers, lattice type I corneal dystrophy, and Avel-
lino corneal dystrophy.285
These autosomal dominant disorders are charac-
terized by progressive accumulation of corneal depos-
its beginning in the first or second decade of life.
Granular corneal dystrophy and lattice corneal dys-
trophy are the most common inherited corneal
dystrophies.285 There is considerable overlap be-
tween their clinical and histological characteristics.293
In granular corneal dystrophy, discrete white granu-
lar opacities first appear in the central superior
region of the cornea.292 With time, the number of
deposits increase, extend, and deepen, obscuring
vision. These deposits have been referred to as
“hyalin.” Lattice corneal dystrophy is classified as a
single-organ amyloidosis. Branching linear amyloid
deposits localize to the central cornea and gradually
OCULAR GENETICS: CURRENT UNDERSTANDING
opacify the visual axis.213 Reis-Bücklers corneal dys-
trophy has been classified as a dystrophy of Bow-
man’s layer and the superficial stroma. Early onset,
painful recurrent corneal erosions, and more superfi-
cially localized corneal opacities distinguish it from
granular corneal dystrophy.224 Avellino corneal dys-
trohy is considered a mixed dystrophy as it pre-
sents clinical characteristics similar to both granular
and lattice corneal dystrophy.127
B. MEESMANN DYSTROPHY
Meesmann corneal dystrophy (MCD) is an autoso-
mal dominant disorder that affects only the corneal
epithelium.124 Uniform, round intraepithelial cysts
are usually visible by age 12 months and increase in
number throughout life (Fig. 4). Rupture of these
corneal microcysts in adulthood results in symptoms
of photophobia, contact lens intolerance, and inter-
mittent decreased visual acuity.
In 1997, Irvine et al mapped the keratin 12 gene
(KRT12) to chromosome 17q12 and showed that
dominant negative mutations in the keratin 3 gene
(KRT3) and KRT12 encoding the cornea-specific ker-
atins, K3 and K12, cause Meesmann corneal dystro-
phy.178 Corneal epithelial cells contain intermediate
filament proteins, cytokeratins. During stages of epi-
thelial differentiation, specific pairs of different kera-
tin chains are coexpressed. The keratin pair K3 and
K12 are coexpressed in the most anterior portion of
the cornea epithelium.354
IV. Lens Disorders
Ninety percent of the lens is composed of two
types of protein: soluble (crystallin) and insoluble
proteins (membrane and cytoskeletal proteins).
There are three main families of crystallins. Alpha-
crystallins appear to be molecular chaperones for the
beta- and gamma-crystallins, helping them to fold
properly as they are synthesized and aiding them
in refolding if they denature.170 Beta-crystallins and
gamma-crystallins have similar structures. Their ter-
tiary structures have two domains that contain beta
sheets and the entire proteins are compact and globu-
lar. The transparency of the lens depends on a highly
structured arrangement of lens proteins and lens
fibers.92 An elaborate system of gap junctions, formed
by the connexins, allows access to metabolically inert
cells within the lens. Crystallins, connexins, and de-
velopmental factors (PAX6, PITX3) may all be
responsible for maintaining lens clarity.162 All the
proteins that function in maintaining the clarity of
the lens could be potential candidate genes causing
heritable cataract.
169
The clinical descriptions of heritable cataracts have
been adopted as an outline for this section. Signifi-
cant genetic heterogeneity does exist however, and
so phenotypes do not correlate uniquely with muta-
tions in individual genes. Many factors both environ-
mental and genetic contribute to the formation of
a cataract.
A. ACULEIFORM CATARACT
Aculeiform cataracts are inherited in an autosomal
dominant fashion. Usually needle-like lens opacifica-
tion occurs bilaterally. In 1999, Héon et al screened
for mutations in the crystallins in three unrelated
affected families.164 They found a G to A transition
mutation in exon 2 of the crystallin gamma D gene
(CRYGD), which substituted a histidine for the highly
conserved arginine (R58H). The R58H mutation in-
duces a change in charge, which introduces a hydro-
gen bond that subsequently impairs the proper
folding of the protein by either increasing its rigidity
or altering its stability. The mutation may also destabi-
lize contact between lens fiber cells thereby affecting
maintenance of lens transparency.
B. POLAR CATARACTS
1. Anterior Polar Cataract 1 (CTAA1)
Anterior polar cataracts are characterized by vari-
able dense, white opacities in the anterior lens. They
may be inherited in an autosomal dominant, autoso-
mal recessive, or X-linked fashion.269 Independent
studies support a locus for anterior polar cataracts
on chromosome 14. In 1984, Moross et al described
a family with a balanced translocation t(2;14)
(p25;q24) and anterior polar cataract.284 In 1992,
Miller et al found that the karyotype of an infant
girl with multiple congenital anomalies and unilateral
nuclear cataract was mosaic 46,XX/46,XX,del(14)
(q32.3).272
Arrhythmogenic right ventricular dysplasia
(ARVD), an autosomal dominant disorder, is a major
cause of sudden death at a young age.39,390 ARVD
was mapped to 14q23-24 by Rampazzo et al.333 A locus
for anterior polar cataract has been mapped adjacent
at 14q24-qter.263 Frances et al reported a brother
and sister who had both ARVD and anterior polar
cataracts.128 Their parents were second cousins, but
healthy.
2. Anterior Polar Cataract 2 (CTAA2)
Berry et al reported a locus for autosomal domi-
nant anterior polar cataract at 17p13 in a four-genera-
tion family.44
170 Surv Ophthalmol 49 (2) March–April 2004
3. Posterior Polar Cataract
In 1997, Ionides et al linked a locus for autosomal
dominant posterior polar cataract to 1p in one
family.177 In another four-generation family, a muta-
tion in the crystallin alpha-B gene was found to segre-
gate with autosomal dominant posterior polar
cataract.43 The mutation likely affects posttransla-
tional modification and protein folding.
C. CERULEAN CATARACT
Cerulean cataracts are characterized by variable
coarse deposits that are mostly lamellar and manifest
a combination of white, blue and purple hues. The
phenotype is genetically heterogeneous, in that a
mutation in more than one gene can cause a similar
phenotype.
1. Cerulean Cataract, Type I (CCA1)
Vogt first described cerulean cataract type I in 1922
as blue and white opacifications in a concentric pat-
tern with occasional radially arranged lesions in the
fetal nucleus.399 In 1995, Armitage et al linked a four-
generation pedigree with cerulean cataract to chro-
mosome 17q24.21 In this family, newborns did not
have lens changes until the age of 18 to 24 months.
The authors suggested that cerulean cataracts be
classifed as developmental rather than congenital cat-
aracts. Three possible candidate genes located in the
region of 17q24: the DHP-sensitive calcium channel
γ subunit (CACNLG), the human somatastatin recep-
tor (SSTR2) and the skeletal muscle sodium channel
α subunit (SCN4A0) were excluded by linkage analy-
sis with intragenic DNA repeat polymorphisms. The
galatokinase gene (GALK1) mapped to 17q23-25 was
also excluded as a possible candidate gene.21 More
recently, a population based study has suggested that
mutations in GALK may predispose to adult
cataract.311
2. Cerulean Cataract, Type II (CCA2)
Cerulean cataract type II is an autosomal dominant
form of congenital cataract. Young affected individu-
als have many blue flakes in the peripheral lens and
some spoke-like opacities in the central lens. In 1996,
Kramer et al reported linkage of CCA2 to the beta
cystallin locus by studying a family originally reported
by Bodker et al.52,221 The daughter of two affected first
cousins was born with congenital bilateral microph-
thalmos and microcornea. She was homozygous for
the disease-bearing chromosome. Curiously one indi-
vidual in the family carried the disease chromosome,
but was unaffected. In 1997, Litt et al found a chain-
terminating mutation in the crystallin beta B2
MACDONALD ET AL
(CRYBB2) gene in this family.233 Héon and cowork-
ers found the same mutation in a family with the
Coppock-like cataract phenotype.145
D. COPPOCK AND COPPOCK-LIKE CATARACT
1. Lamellar Zonular Pulverulent Cataract
(Coppock) (CZP1)
The Coppock cataract was the first inherited disor-
der to be linked to an autosome.85 Dominant lamel-
lar zonular pulverulent cataract or Coppock cataract
(CZP1) is characterized by opacities in both the em-
bryonic nucleus and the fetal nucleus. The CZP1
cataract measures about 4 mm in comparison to the
Coppock-like cataract that measures about 2 mm.
Shiels et al found that CZP1 mapped to the same
locus as the GJA8 gene (connexin50).368 A C to T
missense mutation was found in codon 88 of GJA8
that substituted a phylogenetically conserved proline
for a serine (P88S).
2. Coppock-like Cataract (CCL)
Coppock-like cataract is inherited in an autosomal
dominant fashion and is also genetically heteroge-
neous. Clinically, it appears as a dustlike opacity of
the fetal nucleus with frequent involvement of the
zonular lens. In one family, mutation analysis of exon
2 of the crystallin gamma C gene (CRYGC) by Héon
et al revealed in an A to a C transversion, changing
the amino acid threonine to a proline (T5P) in a
highly conserved region.164 The change hypotheti-
cally disturbs protein function and/or the protein’s
interaction with neighboring proteins, as proline
is known as a potent breaker of β-sheets. Impaired
folding of the protein likely leads to lens opacifi-
cation.
E. MARNER TYPE CATARACT (CAM)
In 1949, Marner described a family with 132 af-
fected members in eight generations.253 Affected in-
dividuals presented with zonular cataract although
some had nuclear, anterior polar, or stellate cataract.
The disorder was progressive and anticipation was
suggested (the trait appears to worsen with each gen-
eration). In 1988, Eiberg et al linked the disorder to
the locus for haptoglobin on chromosome 16 in the
family originally studied by Marner.110 Richards et
al258 found probable linkage of a form of congenital
posterior polar cataract described by Maumenee in
1979338 to the haptoglobin locus. It is possible that
these cataracts are allelic; however, further detailed
morphologic studies, linkage studies, and mutational
analysis will be needed to confirm this.
OCULAR GENETICS: CURRENT UNDERSTANDING
F. VOLKMANN TYPE CATARACT (CCV)
Volkmann-type congenital cataract (CCV), is an
autosomal dominant trait named after the Danish
family in which it was originally studied.238 The disor-
der is progressive with central and zonular cataract.
Opacities are found in the embryonic, fetal, and juve-
nile nucleus and around the anterior and posterior
Y-suture. Variable expression is seen ranging from
barely visible opacities to dense cataracts.
The CCV locus is telomeric to the gene for glucose
dehydrogenase, which maps to 1pter-p36.13.109
The enolase-1 gene (ENO1) is in the same region
as CCV. ENO1 encodes tau-crystallin; however, ENO1
may not be a candidate gene as a family with heredi-
tary red cell enolase partial deficiency did not have
cataracts.227
A genetic variant of the Rh blood group system,
known as the Evans phenotype or the D phenotype
maps to chromosome 1p34-36.79,244 The Evans
phenotype has been linked with a cataract-causing
locus by Huang and coworkers.172,173 Rh polypeptides
of human erythrocytes are polymorphic in nature.
They may have a role in membrane structure and
physiology.5,16,73
G. DOMINANT ZONULAR PULVERULENT
CATARACT (CZP3)
Dominant zonular pulverulent cataract is charac-
terized by fine, dust-like opacities in various regions
of the lens.246 In 1997, Mackay et al found linkage of
this disorder to chromosome 13q in a five-generation
English family.245 In 1996, Mignon et al had mapped
the gene for gap-junction protein α-3 (GJA3, con-
nexin46) to 13q11-q12.270 GJA3 had been found to
be highly expressed in the lens.315 In 1999, Mackay
et al uncovered mutations in GJA3 in two families
with CZP3.246 Further evidence that mutations in the
GJA3 gene cause CZP3 was provided by Rees et al.335
H. AUTOSOMAL DOMINANT NONNUCLEAR
POLYMORPHIC CONGENITAL CATARACT
In 1996, Rogaev et al studied a seven-generation
family of 103 individuals affected with autosomal
dominant nonnuclear polymorphic congenital cata-
ract.344 Patients ranged in age from a few months to
70 years and all presented with congenital cataract.
Opacities varied in shape, number, location, and
color (crystal-like to snow-white). Linkage studies
using a trinucleotide microsatellite marker in the
crystallin gamma 1 gene (CRYG1) mapped this cata-
ract locus to chromosome 2q33-q35.
I. ZONULAR CATARACT WITH SUTURAL
OPACITIES
Zonular cataract is the most common congenital
cataract.314 Opacities are found in a discrete layer of
171
fiber cells while the fibers internal and external to
the opacity remain clear. Opacification may be dense,
uniform, opaque or dotted/dustlike. The sutural
opacities are at juxtaposed ends of secondary lens cells
and often resemble the letter Y. These cataracts can
be inherited in either a dominant or an X-linked
pattern. In 1995, Padma et al studied a three-genera-
tion family with an unusual form of autosomal domi-
nant zonular cataracts with sutural opacities.314
Linkage was found between the cataract and mark-
ers on chromosome 17q11-q12 near the crystallin
beta A1 gene (CRYBA1). In 1999, Kannabiran and
colleagues studied the same family and found a muta-
tion in the CRYBA1 gene, resulting in the deletion
of exons 3 and 4.197 A second family with cataracts
and a mutation in CRYBA1 has been reported by
Bateman and colleagues.29
V. Glaucoma
A. PRIMARY OPEN-ANGLE GLAUCOMA
Primary open-angle glaucoma (POAG) is the most
common form of glaucoma, accounting for approxi-
mately 3% of visual impairment in white and 7.9%
of African Americans.330,331 POAG has been divided
into two groups: juvenile and adult, with overlapping
clinical presentations. Juvenile onset POAG is a rarer
form that typically affects individuals between age 3
and 20, and exhibits an autosomal-dominant pattern
of inheritance.
Juvenile-onset POAG (GLC1A) was first mapped
to 1q21-31.339,366 Stone and colleagues identified mu-
tations in a candidate gene that mapped to this
region, in patients with the POAG.384 The protein
encoded by this gene had been independently char-
acterized as “trabecular meshwork-induced gluco-
corticoid response protein” (TIGR) in trabecular
meshwork cells in culture.115,303 The same protein,
named myocilin, had also been localized to the outer
segment cilium of photoreceptors by Kubota and
colleagues.223
Wiggs et al studied 152 affected families with juve-
nile-onset and adult-onset POAG. They found muta-
tions in the TIGR/myocilin gene were an uncommon
cause of adult-onset (⬍5%) and juvenile-onset (8%)
POAG.417 These results are consistent with the ge-
netic heterogeneity seen in adult-onset POAG. The
recent discovery of a gene, optineurin, involved in
normal tension glaucoma and POAG, adds to the
inventory.336
B. CONGENITAL GLAUCOMA
Primary congenital or infantile glaucoma (GLC3)
occurs in early childhood, usually within the first year
of life, but may develop later up to 3 years of
172 Surv Ophthalmol 49 (2) March–April 2004
age. It is usually inherited as an autosomal recessive
trait. Sarfarazi et al mapped a locus for primary con-
genital glaucoma, GLC3A, to 2p21.350 Mutations in
the gene for cytochrome P4501B1 (CYP1B1) were
identified in families that showed linkage to 2p21,
and likely account for most cases of autosomal reces-
sive congenital glaucoma.380 The CYP1B1 gene be-
longs to the P450 group of monoxygenases involved
in the metabolism of a variety of substrates. A cyto-
chrome P450-dependent arachidonic acid metab-
olite inhibits Na⫹, K⫹-ATPase in the cornea and
may regulate corneal transparency and aqueous
humor production.357
Mapping studies in eight families with congenital
glaucoma has revealed a second locus, GLC3B, at
1p36.7 The gene for GLC3B has yet to be cloned.
C. PIGMENT DISPERSION SYNDROME
In pigment dispersion syndrome, pigment gran-
ules from the iris pigmented epithelium are depos-
ited on various ocular structures, including the
trabecular meshwork. The disorder most frequently
affects young myopic individuals. In 1981 Scheie and
Cameron documented autosomal dominant inheri-
tance in pigment dispersion syndrome.353 Two loci
for pigment dispersion syndrome have been iden-
tified at 7q35-q3615 and at 18q11-q21.14 Although
pigment dispersion syndrome is considered to be
a secondary glaucoma, identification of the genes
causing this condition may have a direct relationship
with the pathogenesis of POAG.
VI. Vitreo-Retinal Disorders
A. NORRIE DISEASE AND ASSOCIATED
CONDITIONS
Norrie disease (ND) is an X-linked recessive disor-
der characterized by congenital blindness due to bi-
lateral congenital retinal dysplasia that progresses to
phthisis bulbi. Progressive sensorineural deafness
occurs in at least 25% of cases.405 The gene for ND
(NDP) was mapped to Xp11.3 and encodes a protein
called norrin whose function is yet to be eluci-
dated.42,78 Computer modeling of norrin suggests
the presence of a so-called cysteine-knot motif, a ter-
tiary structure commonly seen in members of the
growth factor protein superfamily.268 Six conserved
cysteine residues in the carboxy-terminus of the pro-
tein seem to be essential to assure proper folding by
forming three disulfide bridges. Early reports of X-
linked microphthalmia may have been Norrie dis-
ease; however a locus at Xq27-28 distinct from NDP
does exist.151
Familial exudative vitreoretinopathy (FEVR) is a
vitreoretinal dystrophy characterized by premature
MACDONALD ET AL
arrest of vascularization of the peripheral retina.363
It is inherited as an autosomal dominant or X-linked
recessive trait with high pentrance and variable ex-
pressivity. Mutations in NDP have been identified in
X-linked FEVR.77 Missense mutations in NDP may also
play a role in the development of severe retinopathy
of prematurity.364 The dominant form of FEVR maps
to 11p13 and has been shown to be due to mutations in
frizzled-4 (FZD4).343
B. RETINOSCHISIS
X-linked retinoschisis (RS) is the most common
juvenile macular dystrophy seen in males. A cystic
spokewheel maculopathy occurs in virtually all af-
fected individuals as young as three months of age
and may already be present at or before birth (Fig.
5). Approximately 50% of the patients have bilateral
schisis cavities in the peripheral retina (Fig. 6). A
reduced b wave amplitude is recorded with electroret-
inography. Affected males lose vision typically in the
second decade of life. Vision thereafter remains
stable through middle age with a further later decline
to legal blindness.369 Complications may include vit-
reous hemorrhage and retinal detachment.
From clinical observations, the underlying cause
of RS was thought to be a defect in the Müller cell,
a glial cell of the retina which may play a role in
the organization of the retinal architecture during
development.77,352 Histopathology of eyes affected by
RS reveals splitting of the nerve fibre layer of the
retina, degeneration of the photoreceptors, thinning
of the ganglion cell layer and a focal absence of
the retinal pigment epithelium. Sauer and coworkers
identified a gene for RS at Xp22.2, designated
RS1.352 The RS1 protein is expressed in rod and cone
photoreceptors, and bipolar cells but not Müller
cells.278 The predicted protein sequence contains
a highly conserved discoidin domain implicated in
cell–cell adhesion and phospholipid binding
domain, a function consistent with the observed split-
ting of the retina in RS patients.352 Interestingly,
mutation analysis has shown a significant rate of new
mutations in RS.1
C. WAGNER DISEASE
Wagner described a Swiss pedigree in 1938 with
myopia, early cataract formation, liquefaction of the
vitreous, retinal vascular changes and retinal pigmen-
tary alterations.402 Clinicians disagreed in the past
as to whether Wagner disease was separate from
Stickler syndrome (hereditary arthro-ophthalmopa-
thy). Stickler syndrome has extraocular manifes-
tations: skeletal anomalies, micrognathia, deafness
and eye findings: microphthalmia, anterior segment
OCULAR GENETICS: CURRENT UNDERSTANDING 173

Fig. 1. Aniridia with lens opacities and iris stump barely Fig. 3. Gonioscopic view of the anterior segment in irido-
visible. goniodysgenesis.

dysgenesis, high myopia, congenital glaucoma, cata-

ract, and lens luxation. The distinctness of these con-
ditions was established when Wagner disease was
localized to 5q.66 Stickler syndrome was shown to be

Fig. 4. Meesmann dystrophy with intraepithelial cysts dem-

onstrated by retroillumination.

Fig. 2. Pupil corectopia, partial thickness iris stromal holes,

and anteriorly displaced Schwalbe’s line in a patient with
Axenfeld-Rieger malformation. Fig. 5. Foveal schisis in a patient with retinoschisis.
174 Surv Ophthalmol 49 (2) March–April 2004
caused by mutations in the gene encoding the alpha-1
chain of type II collagen (COL2A1) found in vitreous
and cartilage.131
Wagner disease is an autosomal dominant vitreore-
tinal degeneration without extraocular findings.
Clinical expression varies from unaffected carriers to
bilateral severe visual impairment. Erosive vitreoreti-
nopathy (ERVR) is a condition very similar to Wagner
disease. Retinal detachment occurs more frequently
in ERVR. Brown and colleagues presented linkage
evidence that ERVR and Wagner disease were allelic
disorders; both mapping to 5q13-q14.66 IN 1999 Per-
veen et al refined the genetic and physical localiza-
tion of Wagner disease locus to 5q14.3.322
D. ALBINISM
Albinism may be classified as oculocutaneous albi-
nism (OCA) affecting eyes, hair, and skin, and ocular
albinism (OA) affecting only the eyes. OCA is an
autosomal recessive disorder with at least ten vari-
ants and can be subclassified into two categories
according to the presence or absence of tyrosinase ac-
tivity in melanocytes: tyrosinase-negative OCA (OCA
type I) and tyrosinase-positive OCA (OCA type
II).225, 424
1. Tyrosinase-related (OCA type I, OCA1)
OCA type IA, is the most severe form of albinism,
marked by profound hypopigmentation, photopho-
bia, nystagmus, and a propensity to develop malig-
nant skin tumors. It is caused by mutations in the
tyrosinase gene. The variants of tyrosinase-negative
OCA: the yellow mutant (type I-B) and tempera-
ture-sensitive mutant (type I-TS) have some residual
enzyme activity and varying amounts of melanin are
produced in hair, skin, and eyes.143,209
2. Tyrosinase-positive (OCA type II, OCA2)
OCA type II is an autosomal recessive disorder
characterized by no production of the brown-black
pigment (eumelanin) in skin, hair, and eyes.376,423,425
Production of the yellow/orange pigment (pheome-
lanin) does occur in these tissues and accumulates
with age so that infants may initially appear to be
as severely affected as patients with OCA type I, but
they acquire pigment during early to mid childhood.
Visual deficits are generally less severe in OCA type
II than in OCA type I patients. Ocular features of
affected individuals with OCA type II are similar to
those of OCA type I (iris transillumination, dimin-
ished or absent foveal reflex (Fig. 7), misrouting of
the optic tracts, strabismus, nystagmus, and photo-
phobia).86
MACDONALD ET AL
By studying Bantu subjects in South Africa, Ramsay
et al localized the OCA type II locus to 15q11.2-
q12.334 The pink-eye dilution locus (p) on mouse
chromosome 7 mapped to a region of synteny with
human 15q. As such, they postulated that the OCA
type II gene was homologous to the mouse pink-eye
dilution gene, p. This hypothesis was confirmed in
1992 when Gardner and coworkers isolated the
human homologue, P, of the murine p cDNA and
found that it mapped to chromosome 15q11.2-q12.140
The P gene encodes an integral membrane
transporter protein in melanosomes and exhibits
structural homology to transporters of small organic
molecules. Rinchik and coauthors hypothesized that
the protein encoded may have a role in transporting
tyrosine, the precursor to melanin biosynthesis.340
3. Brown Oculocutaneous Albinism
(BOCA, OCA3)
BOCA is characterized by a moderate reduction
in pigmentation in African or African-American indi-
viduals.2,54 A mutation in the mouse brown (b) gene,
results in a mouse with a brown coat color instead
of black.158,179 The protein 5,6-dihydroxyindone-2-
carboxylic acid (DHICA), encoded by the b gene,
was termed the tyrosinase-related protein (TYRP-1)
due to its similarity to tyrosinase. The human TRYP-
1 gene mapped to chromosome 9p23.80,84,287,294,435
In 1996, Boissy and coworkers found a single base
deletion in exon 6 of the TYRP-1 gene in African
American fraternal twins (one normal and one with
BOCA).55 The mutation deleted an A in codon 368,
resulting in a premature stop codon at 384. Since
the TYRP-1 transcript was not detected in OCA mela-
nocytes using various TYRP-1 probes, it was hypothe-
sized that there was a decrease in stability of the
truncated protein.
Despite evidence that implicated the TYRP-1 gene,
Manga and colleagues reported nine southern Afri-
can patients with BOCA who had a deletion at the
locus of the P gene.250 Although disease-causing mu-
tations in the P gene could not be found in the other
allele, a suggestion was made that BOCA may also
be due to mutations in the P gene.
4. OCA4
Another form of oculocutaneous albinism, OCA4,
has been identified through candidate gene analysis.
The mouse gene, underwhite (uw), when carried as a
homozygous mutation causes severe hypopigmen-
tation. In a screen of 102 patients with OCA who did
not have mutations in TYR or the P gene, a single
patient was found with a homozygous single base pair
change in the human ortholog of uw that encodes a
membrane associated transporter protein.302
OCULAR GENETICS: CURRENT UNDERSTANDING
5. Ocular Albinism
Ocular albinism (Nettleship-Falls) is an X-linked
trait with findings predominantly restricted to the
eye: iris transillumination, nystagmus, and foveal hy-
poplasia. The female carrier state of fundus-wide
coarse RPE granularity led Falls117 to anticipate the
Lyon hypothesis of random inactivation of one X
chromosome in clonal cells of female carriers.240
Bassi and colleagues isolated a novel transcript
from Xp22.3-p22.2 where ocular albinism had been
mapped and subsequently identified mutations in this
gene in patients.27 At first this protein was identified
as simply a novel protein. Schiaffino and colleagues
then reported its similarity to a group of G-protein-
coupled receptors that function in intracellular
transport.355
E. COLOR VISION DEFECTS
1. Pigment Genes
The visual pigment genes consist of the rod pig-
ment gene, rhodopsin, and the three cone pigment
genes.298 There is significant homology between the
rhodopsin gene and the three cone pigment genes,
suggesting that all four genes are derived from a
common ancestral gene.301 In fact, the DNA se-
quences and the intron/exon organization of the red
and green pigment genes are almost identical.
The genes encoding the red and green pigments
have been examined by Southern blotting of geno-
mic DNA from several color-normal males.298 The
red pigment is always present in a single copy, but
the green pigment is present as one, two, or three
copies in a head-to-tail array on the X chromo-
some.298 The high degree of relatedness of these
tandem genes and their close physical proximity
often results in mispairing, unequal homologous re-
combination during meiosis, and changes in copy
number.298,299
Human color vision is due to the absorption of
light by three classes of cone photoreceptors with
overlapping sensitivities at short wave lengths (blue),
middle wave lengths (green) and long wave lengths
(red) with maxima at 420, 530, and 560 nm, respec-
tively.300 Inherited color-vision deficiencies are con-
genital and nonprogressive conditions. The common
X-linked forms of color-vision anomalies are often re-
ferred to as red-green color deficiency, a reduced
ability to match or discriminate colors in the mid-to
long-wavelength spectrum and are due to mutations
in the red and green cone pigment genes.301
The term tritanopia indicates weak or absent
discrimination of short-wavelength blue-yellow stim-
uli. Inherited tritanopia is unique among color-vision
deficiencies because of its autosomal dominant trans-
mission. Analysis of the blue-cone pigment in a small
175
group of families with tritanopia revealed a heterozy-
gous missense mutation in the blue cone pigment
gene on chromosome 7 which cosegregated with
the disease.413,414
2. Blue Cone Monochromacy
Blue cone monochromacy (BCM) is a rare X-
linked recessive condition, sometimes mistaken clini-
cally for rod monochromacy. BCM results from lack
of both red and green cone sensitivities, and does not
involve the blue cone pigment gene on chromosome
7.296 The physiologic functions of both rods and
blue cones are preserved. Individuals with BCM have
very poor or absent color discrimination, photopho-
bia, reduced visual acuity (20/70–20/100), and pen-
dular nystagmus. Visual acuity may improve slightly
and nystagmus subside by adulthood.
Linkage of BCM to the red-green pigment locus
(Xq28) was established by Lewis.230 Multiple classes of
mutations can lead to BCM.297 Many patients carry
only a single red or hybrid pigment gene with a mis-
sense mutation. Some patients have up to three pig-
ment genes, each with a missense mutation. Others
have various sized deletions of the proximal part of
the red/green cone pigment gene cluster, the locus
control region (LCR) that controls the expression of
the red/green color genes. In all such cases, the
deletion inactivates the adjacent red/green genes.
3. Rod Monochromacy
Total color deficiency is also referred to as com-
plete achromatopsia or rod monochromacy. It is
the severest form of color-vision deficiency, with a
complete lack of color discrimination. Clinically,
patients have marked reduction in visual acuity, and
pronounced photophobia. Electroretinographic re-
cordings confirm the complete lack of cone photo-
receptor responses.
Four distinct loci have been mapped for rod
monochromacy. The first locus was inferred in a 20-
year-old white female with a 14;14 Robertsonian
translocation.320 She was found to have maternal
isodisomy. This finding suggested that a form of
rod monochromacy mapped to chromosome 14 and
supported the concept that uniparental isodisomy if
found could provide a putative chromosomal assign-
ment for a rare autosomal recessive disorder. Linkage
analysis in a large inbred Iranian Jewish family
showed a second locus for achromatopsia at 2q11.19
This region contained a candidate gene encoding the
cone cyclic nucleotide-gated cation channel alpha
3 subunit (CNGA3). Mutation analysis of CNGA3
revealed missense mutations that cosegregated with
color deficiency in the families analyzed.422 This gene
is also mutated in forms of incomplete achromatopsia
176 Surv Ophthalmol 49 (2) March–April 2004
and cone dystrophy.421 A third gene has been impli-
cated in achromatopsia, GNAT2, which encodes the
cone photoreceptor-specific alpha-subunit of trans-
ducin, a G protein of the phototransduction
cascade.217
Pingelapese blindness is better known as total color
deficiency with myopia. The isolate was described
initially by Brody and coworkers.65 The Pingelapese
live on the eastern Caroline Islands in the Pacific.
Clinically, they have severe photophobia, horizontal
pendular nystagmus, amaurosis, and color defi-
ciency, and gradually develop cataracts. Winck and
colleagues performed a genome wide scan for link-
age in Pingelapese kindred and identified a locus at
8q21-q23.418 Sundin and coworkers subsequently
found that the genetic basis of Pingelapese achroma-
topsia is a recessive point mutation in the CNGB3
gene encoding the β subunit of the cone cyclic nucle-
otide gated channel.387
F. RETINITIS PIGMENTOSA
Retinitis pigmentosa (RP) is a heterogenous group
of retinal degenerations affecting approximately
1:3000 people and responsible for visual loss of 1.5
million people worldwide. Clinically, these disorders
are characterized by night blindness, progressive
loss of peripheral vision, and pigmentary changes in
the retina, eventually leading to complete loss of
vision (Fig. 8). The genetics of RP is complex with
autosomal dominant, autosomal recessive, X-linked,
and digenic patterns of inheritance. A retinal dystro-
phy that mimics RP may also be seen in association
with mutations of the mitochondrial DNA. Over 50
responsible loci/genes have been mapped and/or
characterized (RetNet database; www.sph.uth.tmc.edu/
RetNet/disease.htm) by positional cloning, candi-
date gene approaches and deletion mapping. Many
genes code for photoreceptor-specific proteins that
play key roles in phototransduction and outer seg-
ment morphogenesis. Despite the large number of
identified loci, a molecular defect cannot be found
in more than 50% of patients with RP.
1. Autosomal Dominant RP
Autosomal dominant RP (adRP) accounts for 20%
of all RP cases and is characterized by significant
allelic and non-allelic heterogeneity. In 1990, Dryja
and coworkers first reported that a P23H mutation
in RHO was responsible for a form of adRP.106 Since
that time more than 70 different RHO mutations
have been linked to adRP and arRP. RHO muta-
tions make up to 30% of all adRP.
Mutations in the RDS gene that encodes periph-
erin have been found mostly in families with adRP,
although in some patients, mutations in this gene
MACDONALD ET AL
result in macular degeneration, pattern macular dys-
trophy, fundus flavimaculatus, cone-rod dystrophy,
or bull’s eye maculopathy.232 Different diagnoses
have been assigned to relatives with the same muta-
tion. Mutations in RDS account for about 5% of cases
of adRP.
Mutations in the NRL gene cause adRP. NRL, lo-
cated at 14q11.2, encodes a basic motif-leucine zipper
DNA-binding protein that is highly and specifically
expressed in adult retina. This gene has been shown
to upregulate the activity of the rhodopsin promoter
when it acts synergistically with the homeobox
gene CRX.46
RP13, a form of adRP, located at 17p13.3, is due
to mutations in the pre-mRNA processing factor
gene, PRPF8.262 This gene encodes a highly con-
served splicing factor that is expressed ubiquitously.
This new gene offers compelling evidence for a novel
pathway to retinal degeneration. PRPF31 is another
pre-mRNA splicing gene. Mutations in this gene un-
derlie adRP (RP11).398 RP11 is mapped to 19q13.4.8
Fascin is a protein specific to photoreceptors that
acts to cross link actin into bundles.347 It is likely
involved in the formation of the cilium connecting
the inner and outer segments of rods and cones; and
therefore may affect the formation of new discs. Mu-
tations of the human retinal fascin gene (FSCN2)
were predicted to underlie some forms of retinal
degeneration and may cause 3.3% of adRP in
Japan.401
The RP1 gene is the human homologue of the
mouse rp1 gene that encodes a photoreceptor pro-
tein whose expression is modulated by oxygen levels.
This gene mapped to the pericentric region of chro-
mosome 8, previously identified as a locus for adRP
in a large family from the the southeastern US.51 A
mutation was found in this gene in the original family
and three other families.327
2. Autosomal Recessive RP
To date, at least 14 genes and an additional six
chromosomal loci have been identified for autosomal
recessive RP (arRP). Not surprisingly, genes involved
in the pathway of phototransduction are repre-
sented: rod cyclic nucleotide-gated channel alpha-
subunit (CNGA1); the alpha and beta-subunits of rod
cGMP-specific phosphodiesterase (PDE6A, PDE6B);
and arrestin (SAG). In addition, genes involved in
the pathway of vitamin A metabolism and its recycling
in the eye underlie some forms of arRP: In cellular
retinaldehyde-binding protein (RLBP1); retina-spe-
cific ATP-binding cassette transporter (ABCA4); and
lecithin retinol acyltransferase (LRAT). Mutations in
the RPE-retinal G- protein coupled receptor (RGR)
were found in two cases of RP by Morimura and
OCULAR GENETICS: CURRENT UNDERSTANDING
colleagues.282 RGR binds all-trans-retinol preferen-
tially. Lecithin retinol acyltransferase (LRAT) acts to
form 11-cis retinal from all-trans retinol in the retinal
pigment epithelium. Mutations in this gene were
found in three cases of retinal dystrophy, 2 of which
clearly showed consanguinity.391
3. X-linked RP (Fig. 9)
X-linked RP (xlRP) is genetically heterogeneous
with at least 5 loci: RP2, RP3, RP6, RP23, and RP24.
The first locus, RP2, was localized by linkage analysis
to Xp11.3.48 The RP2 gene has been cloned and
mutations in this gene may account for about 15–
20% of xlRP families.160 A second locus, RP3, was
mapped to Xp21.1 and accounts for 70% of affected
xlRP families.290 The RP GTPase regulator gene
(RPGR) was cloned from the Xp21.1 region by posi-
tional cloning.397 Another locus, RP15, was suggested
at Xp22.13-22.11 in linkage analysis studies of a single
family with X-linked dominant cone-rod dystro-
phy.261 Re-examination of a family member and anal-
ysis of the pedigree allowed the identification of a
mutation in RPGR, allowing reclassification of the
phenotype.265
4. Digenic RP
Digenic inheritance, the interplay of mutations in
two different genes resulting in a heritable eye disor-
der, is an important genetic concept. Families with
digenic RP have mutations in both RDS and the
ROM1 gene.26,105 Affected individuals in these fami-
lies are heterozygous for mutations in both genes.
Their parents are heterzygous carriers of either a
ROM1 or RDS mutation and are phenotypically
normal. The pattern of inheritance mimics an auto-
somal recessive trait, when looking at the parental
generation. Affected individuals may then transmit
the disorder like a dominant trait, but the transmis-
sion ratio is 25% rather than 50%, as both muta-
tions must be transmitted to the offspring in order
for them to be affected.
5. Usher Syndrome
Usher syndrome (USH), is characterized by hear-
ing impairment and RP, and is transmitted as an
autosomal recessive trait. Three broad patterns have
been recognized in families: Usher syndrome type I
(USH1) characterized by congenital and severe-to
profound hearing impairment with vestibular dys-
function; Usher syndrome type II (USH2), with early
age moderate to severe hearing loss and normal ves-
tibular function; and Usher syndrome type III
(USH3), with adult onset progressive hearing loss.
USH affects one child in 25,000 in the U.S.59 It
is regarded as the most frequent cause of hereditary
177
deaf-blindness. Six USH 1 loci, USH1A, 1B, 1C, 1D,
1E and 1F have been mapped to chromosomes
14q32, 11q13.5, 11p15.1, 10q21-q22, 21q21 and
10q21-22, respectively.
At present, five USH1 genes have been cloned:
myosin VIIA, harmonin, a cadherin-like adhesion
protein, protocadherin and usherin. USH1 is re-
ported to be responsible for half of the Usher cases.
The USH1B gene accounts for 75% of USH1 cases,
and codes for myosin VIIA, a putative actin-based
motor protein.410 The gene is expressed in the co-
chlear and vestibular hair cells as well as in the retinal
photoreceptor and pigment epithelial cells from
embryonic life onwards. Harmonin, the gene under-
lying USH1C, is a PDZ-containing protein expressed
in the inner ear sensory hair cells.49, 396 The PDZ
domain was named after three proteins that were
first shown to contain this domain (PSD-95, DLG
and Z0-1). Independently, Bolz and colleagues,56 and
Bork and coworkers58 (2001) identified the gene for
USH1D, CDH23. It is expressed in the retina and
cochlea and encodes an intercellular adhesion pro-
tein. Mutations of protocadherin 15 have been found
to cause USH1F.6
The gene for USH2A at 1q41 encodes a protein,
usherin, that has laminin, epidermal growth factor
and fibronectin motifs. These motifs are most com-
monly observed in proteins of the basal lamina, the
extracellular matrix, and cell adhesion molecules.
USH2C maps to 5q14-21.326 The gene for USH3
maps to 3q21-q25 and encodes a novel protein with
transmembrane domains.186
6. Leber Congenital Amaurosis
Leber congenital amaurosis (LCA) is a group of
retinal degenerations that are recognized at birth or
during the first few months of life. An infant presents
with total blindness or greatly impaired vision, nystag-
mus, an extinguished electroretinogram (ERG) and
a range of fundus findings (Fig. 10). Many of the
children develop a characteristic eye poking behavior
(digito-ocular sign of Franceschetti). Hypermetropia
and keratoconus frequently develop in the course of
the disease. It is inherited as an autosomal recessive,
rarely as an autosomal dominant trait. While six genes
have been identified as mutated in cases of LCA, the
genetics of the majority of cases remains unresolved.
The first gene for LCA was mapped to chromo-
some 17p13.1 (LCA1).321 Using a candidate gene
approach, mutations were identified in the photo-
receptor-specific guanylate cyclase gene (GUCY2D).
Mutations in GUCY2D result in impaired production
of cGMP in the retina, with permanent closure of
cGMP-gated cation channels. Consequently, the
cGMP concentration in photoreceptor cells cannot
178 Surv Ophthalmol 49 (2) March–April 2004
be restored to the dark level, leading to a state equiva-
lent to constant light exposure.
Mutations in RPE65 cause LCA.252 The gene en-
codes a 65-kD protein specific to the retinal pigment
epithelium (RPE). RPE65 is believed to act as the
isomerase catalyzing the conversion of all-trans-reti-
nyl-ester to 11-cis-retinol in the RPE, an essential step
in the metabolism of vitamin A. RPE65 maps to 1q31.
RPE65 gene therapy in the Briard dog restored visual
function, and efforts are now underway to develop a
human gene therapy.3
Mutations in CRX, a novel photoreceptor-specific
homeobox gene (19q13.3) have been found in au-
tosomal dominant RP and recessive LCA.133 LCA3,
has been mapped to 14q24, but the gene remains to
be identified. LCA4 was mapped to 17p13.1 by link-
age analysis. The gene was cloned and encodes the
protein, arylhydrocarbon-interacting receptor pro-
tein-like 1 (AIPL1). The gene is expressed in photore-
ceptors and pineal gland. LCA5 has been mapped
to 6q11-16 by linkage analysis.97 Lotery and coworkers
described novel mutations in the crumbs homolog 1
gene (CRB1) that cause LCA.235 Finally, a novel gene
called RPGIP1 for RPGR-interacting protein is lo-
cated at 14q11.102 Recessive mutations in this gene
cause a degeneration of both rod and cone photo-
receptors early in life with typical signs of LCA.102
7. Retinitis Punctata Albescens (RPA)
Retinitis punctata albescens is a form of night
blindness in which the fundus shows discrete uniform
white dots or flecks with greatest density in the mid-
periphery and no macular involvement. Both autoso-
mal dominant and autosomal recessive modes of
inheritance have been suggested. An autosomal dom-
inant form has been linked to a mutation in the RDS
gene.195 A phenotype similar to RPA is also seen in
Bietti crystalline corneoretinopathy (BCD) which is
inherited as an autosomal recessive. BCD has been
mapped to 4q35-tel.185 Autosomal recessive RPA is
due to mutations in RLBP1, the gene encoding cellu-
lar retinaldehyde-binding protein.69
8. Congenital Stationary Night Blindness (CSNB)
CSNB comprises a group of disorders character-
ized by congenital onset of nonprogressive nyctalo-
pia, subnormal visual acuity, and absence of
pigmentary degeneration of the retina. Strabismus
and nystagmus are often associated with this group of
disorders.37 Three monogenic modes of inheritance
have been described: autosomal dominant, autoso-
mal recessive, and X-linked recessive.
Electroretinography (ERG) has a key diagnostic
role in CSNB. CSNB has been divided into the Riggs
MACDONALD ET AL
type and the Schubert-Bornschein type or negative-
type ERG. The Riggs type ERG (with no a wave) is
seen in the autosomal dominant form of CSNB. In
this form of CSNB, Dryja and colleagues reported a
mutation in the gene encoding the alpha subunit of
rod tranducin (GNAT1), the G-protein that couples
rhodopsin to cGMP-phosphodiesterase in the photo-
transduction cascade.104 GNAT1 is located at 3p21.
The absence of the rod a wave in this form of station-
ary night blindness is used as evidence of physiologic
effects on the rod photoreceptor. The Schubert-
Bornschein type ERG has a normal a wave, but re-
duced or absent b wave. The Schubert-Bornschein
ERG suggests normal rod function but a deficit at the
level of bipolar cell layer or the synaptic connection
between rod photoreceptors and the bipolar cells.291
Clinical heterogeneity among families with CSNB
led to the suggestion that the X-linked form of
CSNB be classified as either complete (CSNB1) or
incomplete (CSNB2).35 The classification was based
on abnormalities both of the ERG and dark-adapta-
tion thresholds. In the complete form of CSNB, both
the scotopic b wave recorded in response to dim blue
flashes and the early oscillatory-potential wavelets
are nonrecordable. The night blindness is profound,
as documented by the lack of rod adaptation to dark-
ness.291 In the incomplete form of CSNB, the scotopic
b wave is recordable, although it is subnormal in
amplitude. The dark-adaptation thresholds are only
slightly elevated above normal.291 Genetic analyses of
families with X-linked CSNB supported two loci, one
for complete (CSNB1) mapped to Xp11.4-p11.3 and
a second locus for incomplete type of CSNB (CSNB2)
mapped to Xp11.23.61
CSNB2 encodes an L-type voltage-gated calcium
channel, alpha-1 subunit (CACNA1F) and mutations
in this gene result in loss of function.37 The gene for
complete CSNB (CSNB1) encodes a glycosylphos-
phatidylinositol (GPI)-anchored protein, called nyc-
talopin.36 This protein has cystine clusters and 11
leucine-rich repeats, and is a new member of the
small leucine-rich proteoglycan (SLRP) family. The
role of other SLRP proteins suggests that mutant
nyctalopin disrupts developing retinal interconnec-
tions involving the ON-biploar cells, leading to poor
vision in patients with CSNB.36
9. Oguchi Disease
Oguchi disease is a rare autosomal recessive form
of stationary night blindness due to mutations in
either arrestin (S-antigen)135 or rhodopsin kinase.83
These two proteins are members of the rod photo-
transduction pathway. Rhodopsin kinase acts with
arrestin in shutting off rhodopsin after it has been
activated by a photon of light and defects in these
OCULAR GENETICS: CURRENT UNDERSTANDING
Fig. 6. Peripherial schisis in retinoschisis.
genes impair rod sensitivity in dim light. Patients with
this disease show a distinctive golden-brown fundus
coloration that develops as the retina adapts to light,
called the Mizuo phenomenon.
10. Choroideremia
Choroideremia (CHM) is a sex-linked chorioreti-
nopathy in which both carrier females and affected
males show signs of patchy chorioretinal atrophy.
Signs begin earlier in the males in the first decade of
life and are progressive, leading to loss of peripheral
vision. The central macula is preserved until late in
the disorder, but eventually sight is lost. The carrier
Fig. 7. Foveal hypoplasia in tyrosinase positive oculocuta-
neous albinism.
179
Fig. 8. Bone spicule formation and vessel attenuation in
autosomal dominant retinitis pigmentosa.
female usually shows mild signs with no loss of periph-
eral vision and a slow progression of signs. In general,
choroideremia is not clinically confused with RP;
however, the end stages of each disease process may
be remarkably similar.242
The CHM gene encodes Rab escort protein-1,
previously termed component A of geranylgeranyl
transferase.358 REP-1 is necessary for the efficient pre-
nylation of specific Rab proteins in the eye. Rab pro-
teins are small GTPases that function in targeting
Fig. 9. Vessel attenuation and optic nerve head gliosis in
X-linked retinitis pigmentosa.
180 Surv Ophthalmol 49 (2) March–April 2004
of vesicle transport within cells. Another autosomal
gene has been cloned that encodes a protein REP-
2.87 REP-2 is likely not sufficient to allow prenylation
of specific Rab proteins within the eye, accounting
for the progressive chorioretinal degeneration in
both the hemizygous male with mutations in the
CHM gene and the carrier female. All mutations to
date result in a truncation of the normal gene prod-
uct and its absence.
In counseling patients with the presumptive diag-
nosis of CHM, a sex-linked pattern of inheritance
should be sought. Identification of carrier females
can be undertaken with clinical examination. Confir-
mation of the clinical diagnosis may be provided by
direct sequencing of the gene or immunoblot ana-
lysis to demonstrate absence of REP-1 in affected
males.243
G. MACULAR DYSTROPHY
1. Sorsby Fundus Dystrophy
Sorsby fundus dystrophy (SFD) is an autosomal
dominant macular degeneration developing in the
third or fourth decade.375 Central vision is lost as a
result of subretinal neovascularization and subse-
quent atrophy of the choriocapillaris, retinal pigment
epithelium (RPE), and retina. A macular disciform
scar and extension of chorioretinal atrophy to the
fundus periphery may occur in later stages. SFD and
AMD share some clinical features. Similar to early
AMD, in early SFD a confluent, lipid-containing de-
posit accumulates within Bruch’s membrane.63,72
Bruch’s membrane is multilayered, composed of
collagen, laminin, fibronectin, proteoglycans, and
glycosaminoglycans.231 During normal development,
production and turnover of extracellular matrix mol-
ecules involves a family of tightly regulated matrix
metalloproteinases (MMPs) and other proteolytic
enzyme groups such as serine or cysteine protein-
ases.98,256 Remodeling of the extracellular matrix is
an important process and MMP activity is con-
trolled at the level of transcription and enzyme activa-
tion/inhibition.256
Apte et al isolated overlapping cDNAs encoding
TIMP3, a novel member of the family of tissue in-
hibitors of metalloproteinases and mapped it to
chromosome 22q12.1-q13.2.18 TIMPs are a group of
zinc-binding endopeptidases involved in the degrada-
tion of the extracellullar matrix. In 1994, Weber and
colleagues linked SFD to markers on 22q13-qter
and using the candidate gene approach, found point
mutations in TIMP3 in SFD patients from two pedi-
grees.408 The mutations predicted a change in the
tertiary structure of TIMP3, resulting in improper
function of the mature protein. Altered TIMP3 func-
tion would lead to abnormal subretinal deposits, dis-
turbing the balance between buildup and breakdown
MACDONALD ET AL
of the extracellular matrix.408 This deposit may act
as a barrier to diffusion of nutrients to the photore-
ceptors and account for impaired dark-adaptation
in some SFD subjects.72,378 Despite the similarity in
phenotypes between SFD and AMD, no mutations
have been found in the TIMP-3 gene in a screen of
AMD patients.120
2. Stargardt Macular Dystrophy
Stargardt macular dystrophy (STGD) is an autoso-
mal recessive disorder first described in 1909.377
Onset occurs between 7 and 12 years of age, followed
over a period of several months by bilateral loss of
central vision. Depigmentation and atrophy of the
macular retinal pigmentary epithelium (RPE) is usu-
ally accompanied by perimacular yellowish spots
(Fig. 11).125,129,155,377 Peripheral visual fields remain
normal throughout life as degeneration is limited to
the macula. STGD is a frequent cause of macular
degeneration in children with an incidence of 1 in
10,000,50 and accounts for 7% of all retinal dys-
trophies.198
Fundus flavimaculatus (FFM) is characterized by
uniformly distributed yellow spots in the fundus.141
The age of onset of FFM occurs later than STGD,
ranging from 17 to 60 years in adult patients, and its
progression is slower. Symptoms include loss of color
vision, photophobia, paracentral scotoma and slow
dark adaptation. Central vision loss occurs late in
FFM. FFM and STGT are now believed to be allelic
disorders, despite differences in age of onset, clinical
course and severity.141 Linkage studies by Kaplan
et al,10,200 and Gerber et al141 mapped STGD and
FFM, to 1p21-13 and 1p13, respectively. In 1997, a
gene (ABCA4) encoding an ATP-binding cassette
(ABC) transporter was mapped to 1p22 by Allikmets
et al and mutations were found in this gene in STGD
families.10 The ABCA4 gene is expressed in rod and
cone photoreceptors.279 As an example of the value
of understanding phenotype/genotype correlations,
Rozet et al found that nonsense mutations truncat-
ing the ABCA4 gene resulted in STGD, whereas
missense mutations resulted in FFM.345
An autosomal dominant form, Stargardt-like macu-
lar dystrophy, is seen uncommonly. Patients have a
macular dystrophy with peripheral flecks that do not
extend much beyond the central macula. Recently a
gene, ELOVL4, thought to function in the pathway
of very long chain fatty acid synthesis has been found
that is mutated in affected individuals.434
3. Best Vitelliform Macular Dystrophy
Best vitelliform macular dystrophy (BMD, VMD2)
is a slowly progressive macular degeneration with
onset in the teens.148 Typical egg yolk-like macular
OCULAR GENETICS: CURRENT UNDERSTANDING 181

Fig. 13. Leucocoria in a child with retinoblastoma.

Fig. 10. Leber congenital amaurosis with retinal thinning

and vessel attenuation. lesions (Fig. 12), and abnormal electrooculographic
(EOG) findings characterize BMD.91 It is inherited
in an autosomal dominant fashion.148 Although
many patients remain free of fundus abnormalities
throughout life, BMD is considered fully penetrant
because nearly all carriers of the defective gene have
an abnormally low Arden ratio (the light peak to
dark trough of the electro-oculogram).20
In the vitelliform stage, lipofuscin accumulates
within and beneath the RPE, but generally does not
impair visual acuity.409 The egg-yolk lesion in the
macula can remain stable for many years without
affecting vision. Subsequently, in a process called
“scrambling the egg,”62 the macular egg-yolk be-
comes deeply and irregularly pigmented, and visual
acuity is affected. Loss of central vision may eventually
occur as a result of RPE atrophy and/or choroidal
neovascularization.409 In 1992, Stone et al linked

Fig. 11. Central maculopathy of autosomal recessive Starg-

ardt macular dystrophy.

Fig. 12. Yolk-like lesion in Best vitelliform dystrophy. Fig. 14. Dominant optic atrophy.
182 Surv Ophthalmol 49 (2) March–April 2004
BMD to chromosome 11q13.386 Petrukhin et al subse-
quently identified disease-specific mutations in a
novel retina-specific gene, bestrophin.324
H. RETINOBLASTOMA
Retinoblastoma (RB) is an embryonic neoplasm
of retinal origin. Although it is the most common
intraocular malignant tumor of childhood, it is rela-
tively rare (1:20,000 live births)(Fig. 13). About 5%
of RB patients have either a deletion or translocation
at 13q14. The RB1 gene was then cloned from this
region. RB occurs in both hereditary and nonheredi-
tary forms. Whereas 90% penetrance is seen in most
families, families with low penetrance have been re-
ported.234 Molecular genetic techniques of gene am-
plification and DNA sequence analysis have shown
that RB arises from two mutational events.216 Muta-
tion in one allele of the BR1 gene leads to a predispo-
sition for RB. Tumor development is initiated by
inactivation of the second RB1 allele. If both muta-
tions occur in the same somatic or postzygotic retinal
cell, a single, unilateral, noninheritable retinoblas-
toma occurs. In the hereditary form, the first muta-
tion occurs in a germinal cell (gonadal) and the
second mutation in a somatic cell (retina), resulting
in multiple retinal tumors in one or both eyes. Be-
cause every cell in the body has the germ line muta-
tion, the patient is at risk for malignancies at other
sites.
RB1 is a large tumor-suppressor gene of 27 exons.
The protein (pRB) inhibits cell proliferation
through interaction with the transcription factor,
E2F.107 Germ line mutations of RB1 lead to a 40,000
fold relative risk for RB, a 500-fold risk for sarcoma
(increased to 2000 by therapeutic radiation). In the
absence of pRB, cells proliferate, further mutations
occur and a retinal tumor emerges.134,139
Approximately 50% of all cases of RB are heritable.
All patients with familial, bilateral, or unilateral
multifocal RB are regarded as carriers of an RB1
germ-line mutation. In addition, survivors of isolated
unilateral RB may have children affected by RB. Klutz
et al, by using precise molecular studies of RB1 in
the tumor and blood of children with unilateral RB,
showed that 9% of patients with unilateral RB have
a RB1 germ-line mutation.214 Molecular studies can
be important in patients with unilateral RB. These
patients might be the first evidence in a family of
low-penetrance of an RB1 mutation.234 A tumor may
then grow unobserved if relatives have not been
screened. Unfortunately, practical molecular testing
of patients with unilateral RB usually requires that
tumor is available to permit identification of RB1
mutations. Mutation screening of peripheral blood
DNA can however detect oncogenic mutations for
MACDONALD ET AL
most patients with bilateral or familial RB. Although
molecular testing for RB1 mutations is still not freely
available, a comparison of the costs of molecular ge-
netic testing versus infant screening approaches has
indicated that mutation analysis will help reduce
health-care expenses. Whether a case of RB is spo-
radic or familial, first degree relatives are screened
regularly with ophthalmic examinations. Molecular
genetic analysis can remove this burden if an individ-
ual is found to not carry a mutation in the RB1
gene.138,308
I. GYRATE ATROPHY
Gyrate atrophy is an autosomal recessive degenera-
tion of the choroid and retina.389 Clinical manifes-
tations usually start in the first decade with night
blindness and progressive myopia. Small, sharply de-
marcated, circular areas of chorioretinal atrophy
are observed at the age of 5 years.193 Enlargement
of atrophic areas is observed in the second and third
decades, with peripapillary lesions. The optic disc
stays pink and healthy. Hyperpigmentation and occa-
sional crystals can be seen at the margins of the
atrophic areas.192 By the second or third decade of
life, posterior subcapsular cataracts become visible
and surgery is necessary.191 During the later phases
of the disease, but before the atrophy becomes com-
plete, the electroretinogram (ERG) is decreased.
Ornithine-delta-aminotransferase (OAT) is a nu-
clear-encoded mitochondrial matrix enzyme which
catalyzes the reversible interconversion of ornithine
and alpha-ketoglutarate to glutamate semialdehyde
and glutamate. The OAT gene maps to chromo-
some 10q26,24,276,309,310,332 and mutations in this gene
cause gyrate atrophy.394,395 Plasma, urine, spinal
fluid, and aqueous humor ornithine levels are 10 to
20 times higher than normal.370 The mechanism by
which OAT deficiency and hyperornithinemia lead
to chorioretinal degeneration is not known.
J. CONE AND CONE ROD DYSTROPHIES
1. Cone Dystrophy
Although grouped with the cone-rod dystrophies,
X-linked cone dystrophy (COD1) affects primarily
the cone photoreceptors, as witnessed by the ERG.
Affected males have photophobia, myopia, abnormal
color vision, and poor central vision with central sco-
tomas. The ophthalmologic findings show progres-
sion from retinal pigment epithelial changes, to
bull’s eye maculopathy and finally central macular
atrophy.180 Linkage analysis including a large pedi-
gree clearly established COD1 as a separate genetic
disorder mapped to Xp11.4 between RP2 and RP3.362
Some COD-1 families however have mutations in
RPGR that normally cause X-linked RP (RP3).94
OCULAR GENETICS: CURRENT UNDERSTANDING
Another form of cone dystrophy (COD3)
displays an autosomal dominant pattern of inheri-
tance. In a large British kindred, linkage analysis
first mapped the disorder to 6p21.1 and subsequent
molecular genetic analysis of the guanylate cyclase
activator-1A (GUCA1A) found a mutation in all af-
fected family members.317 Intrafamilial variability can
be seen with mutation of the GUCA1A gene with
both cone and cone rod dystrophy phenotypes.101,232
2. Cone Rod Dystrophies
The cone rod dystrophies are inherited in an au-
tosomal dominant or autosomal recessive pattern and
can exhibit various phenotypes including: macular
dystrophy, pattern dystrophy, and severe retinal dys-
trophy.232 This spectrum includes minimally affected
individuals with a late onset disorder to others with
end stage RP within the same pedigree. Electrophysi-
ology, visual field examination, and color vision test-
ing and family history are important to define the
phenotype. The ERG shows a predominant effect on
the cone ERG with a relatively preserved rod ERG
in its early phases. Although many loci have been
suggested, we discuss only 3 for which the genes have
been cloned.
CRX, the cone rod homeobox transcription factor,
has been shown to be mutated in cone rod dystrophy
(CORD2).132 Curiously, this same gene is mutated in
Leber’s congenital amaurosis (LCA4). The CRX gene
is expressed in photoreceptors but it may have a wider
role in the maintenance of neurotransmission in
the retina.232
Using linkage analysis, Kelsell and coworkers
(1997) mapped a locus (CORD6) at 17p13.1,202 and
subsequent molecular studies revealed mutations
in the retinal guanylate cyclase (GUCY2D) gene.204
This is the same gene that is mutated in a form of
Leber’s congenital amaurosis (LCA1) and may ex-
plain the early onset of CORD6 in childhood.152
Some forms of cone rod dystrophy exhibit an au-
tosomal recessive mode of inheritance. ABCA4, the
gene that is mutated in Stargardt macular dystrophy,
is commonly found mutated in autosomal recessive
cone rod dystrophy.257
VII. Optic Nerve
A. DOMINANT OPTIC ATROPHY,
KJER TYPE (OPA1)
Kjer-type juvenile optic atrophy (OPA1) is an au-
tosomal dominant disorder with a frequency of 1 in
50,000.212 OPA1 is characterized by insidious onset
before 8 years of age, reduced central vision, loss of
color perception predominantly in the blue-yellow
axis, temporal or diffuse disk pallor (Fig. 14), and a
slowly progressive course.400
183
Linkage analysis of three Danish families linked
the OPA1 gene to 3q28-q29.108 Other studies have
confirmed this linkage and narrowed the interval,
with no evidence of genetic heterogeneity in
Cuban,239 French,57 British,188 and American fami-
lies.67 OPA1 is due to mutations in a gene that en-
codes a mitochondrial dynamin-related protein,
thought to function in the maintenance of mito-
chondrial morphology.9,93 Mutations in the OPA1
gene are highly penetrant but show variable expres-
sion. Individuals in a family may have visual impair-
ment ranging from mild to severe.
A second locus for dominant optic atrophy was
linked to 18q13.2-q12.3.206 This form of optic atrophy
showed interfamilial variation similar to families
linked to 3q.
B. OCULORENAL SYNDROME AND PAX2
MUTATIONS
Pax2 is expressed in both the uretheric bud and
surrounding mesenchyme of mouse embryos. In the
eye, Pax2 is expressed in the ventral optic stalk,
the portion of the optic vesicle that will generate the
optic nerve, and in the optic nerve head. It is also
expressed in the developing inner ear of the mouse
embryo.349 In humans, mutations in PAX2 have been
identified in patients with the autosomal dominant
oculorenal syndrome of optic nerve colobomas and
renal malformations.12 Auditory and central nervous
system abnormalities may occur. PAX2 mutations can
show extreme intrafamilial and interfamilial variabil-
ity. The gene for PAX2 maps to 10q25.118
C. LEBER HEREDITARY OPTIC ATROPHY (LHON)
LHON is a maternally inherited optic neuropathy
that is associated with mutations in the mitochondrial
DNA (mtDNA).403 The mtDNA encodes for a
number of protein components of the mitochondrial
respiratory chain and oxidative phosphorylation
system, as well as some 20 transfer RNAs and two
ribosomal RNAs. A plethora of mtDNA mutations
have been identified in families with LHON resulting
in confusion as to the pathogenic significance of each
mutation. Five primary mutations at basepairs 3460,
4160, 11778, 14484, and 15257 represent the majority
of mutations in affected families.175 LHON manifests
typically as a painless loss of central vision within the
second and third decade of life. The age of onset
may vary widely from 1 to 70 years.171
The eyes can be affected simultaneously or sequen-
tially, with an average time interval of about 2 months.
Neuro-ophthalmic examination commonly reveals
peripapillary telangiectasia, pseudopapilledema and
vascular tortuosity.304,305 The probability of visual re-
covery varies with the type of mutation: 4% of 11,778
184 Surv Ophthalmol 49 (2) March–April 2004
patients recover 36 months after onset; 22% of 3,460
patients recover after 68 months; 28% of 15,257 pa-
tients recover after 16 months; and 37% of 14,484
patients recover after 16 months.312,341,342
Although LHON is considered to be familial, many
individuals represent isolated cases. Interestingly, in
Asia, greater than 90% of LHON patients harbor the
11778 mutation. Based on reported cases, 50–80%
of males and 8–32% of females who carry a mtDNA
mutation will be at risk of significant visual loss.255
VIII. Eye Development Disorders
A. MICROPHTHALMIA
Microphthalmia may be designated as simple
(without other ocular disease), complex (associated
with cataract, retinal or vitreous disease), or more
complex (with malformations).411,412 Up to 80% of
cases occur as part of syndromes that include systemic
malformations, especially cardiac defects, facial
clefts, microcephaly, and hydrocephaly.196 Microph-
thalmia can be further divided into colobomatous
and non-colobomatous categories on the basis of
associated uveal abnormalities.28,404 Microphthalmia
can be an isolated or familial disorder: autosomal
dominant,346 autosomal recessive,219 and X-linked re-
cessive.151 A locus for autosomal dominant coloboma-
tous microphthalmia has been found at 15q12-q15
in the study of a Sephardic Jewish kindred.283
Many chromosomal anomalies have been associ-
ated with uveal coloboma, micropthalmia, anoph-
thalmia, or a combination of these defects, including:
trisomy 13 (Patau), 4p- (Wolf-Hirschorn), 11q-, 13q-,
18q-, ring 18, trisomy 18 (Edward), cat-eye syndrome
(marker 22) and Klinefelter syndrome (XXY).404
The yield of chromosomal studies is poor in isolated
microphthalmia/coloboma but increases significantly
if there is mental retardation or other congenital
malformation. Prenatal high-quality ultrasonography
may detect microphthalmia.
IX. Conclusion
Ophthalmology has contributed broadly to the
clinical delineation of genetic disorders. In the last
20 years, molecular genetics has uncovered the com-
plexity of ocular genetics. Eye genes are now being
mapped and cloned at an incredible rate. The infor-
mation presented in this paper may provide a
clearer summary of the genetics of heritable ocular
disorders and serve as a starting point in the investiga-
tion of families. More indepth research may be re-
quired to provide an up-to-date understanding of
particular conditions before counseling patients
and families.
The investigation of a single case of a suspected
heritable ocular disorder begins with a careful family
MACDONALD ET AL
history. The examination of other family members
will sometimes provide important clues as to the clini-
cal diagnosis. Supplemental molecular genetic diag-
nosis in some cases can then provide a specific
diagnosis for the index case and the entire family.
Method of Literature Search
The sources of information for this review were
accumulated over a 3-year period (1999–2002) by
hand-searching articles from major ophthalmic-
and genetic journals. Where possible the current
nomenclature and references were verified with
citations in OMIM, RetNet, and Genew.
Databases used:
a. Genew, HUGO Gene Nomenclature Commit-
tee (HGNC), Department of Biology, Univer-
sity College London, Wolfson House, 4
Stephenson Way, London NW1 2HE, UK.
World Wide Web URL: www.gene.ucl.ac.uk/
cgi-bin/nomenclature/searchgenes.pl. Wain
HM, Lush M, Ducluzeau F, Povey S. Genew:
The Human Gene Nomenclature Database.
Nucleic Acids Research 2002 Vol. 30, No. 1
169-171. Accessed October 2002.
b. OnLine Mendelian Inheritance in Man,
OMIM. Center for Medical Genetics, Johns
Hopkins University (Baltimore, MD) and Na-
tional Center for Biotechnology Information,
National Library of Medicine (Bethesda, MD).
World Wide Web URL: www.ncbi.nlm.gov/
Omin/.
c. Retinal Information Network, RetNet. The
Hermann Eye Center, The Human Genetics
Center. The University of Texas Houston
Health Science Center. World Wide Web URL:
www.sph.uth.tmc.edu/retnet/.
d. GeneTests. GeneClinics: Medical Genetics In-
formation Resource (database online). 쑖
1993–2002 University of Washington and Chil-
dren’s Health System. Updated weekly.
Available at www.geneclinics.org or www.gen-
etests.org. Accessed October 2002.
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The authors reported no proprietary or commercial interest in
any product mentioned or concept discussed in this manuscript.
The authors are very grateful for many helpful comments from
Elise Héon, Muriel Kayser-Kupfer, Paul Sieving, and Michael
Walter who read all or part of the manuscript.
Reprint address: Ian M. MacDonald, MD CM, Ocular Genetics
Laboratory, University of Alberta, 832 Medical Sciences Bldg.,
Edmonton, AB Canada T6G 2H7.
Outline
I. Introduction
II. Anterior segment conditions
A. Aniridia
B. Axenfeld-Rieger malformation
C. Peters anomaly
III. Corneal dystrophies
A. βig-h3
B. Meesmann dystrophy
IV. Lens disorders
A. Aculeiform cataract
B. Polar catatact
OCULAR GENETICS: CURRENT UNDERSTANDING 195

1. Anterior polar cataract 1 H. Retinoblastoma

2. Anterior polar cataract 2 I. Gyrate atrophy
3. Posterior polar cataract J. Cone and cone rod dystrophies
C. Cerulean cataract 1. Cone dystrophy
1. Cerulean cataract type I 2. Cone rod dystrophy
2. Cerulean cataract, type II VII. Optic nerve
D. Coppock and Coppock-like cataract A. Dominant pptic atrophy, Kjer type (OPA1)
B. Oculorenal syndrome and PAX2 mu-
1. Lamellar zonular pulverulent cataract
tations
(Coppock)
C. Leber hereditary optic neuropathy
2. Coppock-like cataract
E. Marner-type cataract VIII. Eye development disorders
F. Volkmann-type cataract A. Microphthalmia
G. Dominant zonular pulverulent cataract
H. Autosomal dominant nonnuclear poly- IX. Conclusion
morphic congenital cataract
I. Zonular cataract with sutural opacities

V. Glaucoma Glossary of Terms

A. Primary open-angle glaucoma (In compiling the glossary of terms, the authors
B. Congenital glaucoma referred to www.genomicglossaries.com.)
C. Pigment dispersion syndrome
VI. Vitreo-retinal disorders Allele - one or more alternate forms of a gene.
A. Norrie disease and associated conditions Antisense - the specific sequence of nucleotides that
B. Retinoschisis binds to the sense or coding sequence.
C. Wagner disease Candidate gene approach - the search for mutations
D. Albinism in a known gene in the map location of a genetic trait.
1. Tyrosinase related (OCA1) cDNA - complementary DNA, usually ascribed to the
2. Tyrosinase positive (OCA2) coding sequence of a gene that makes a protein.
3. Brown oculocutaneous (OCA3)
4. Oculocutaneous albinism type 4 Chaperone - a protein assisting in transport.
(OCA4) Contiguous gene syndrome - a deletion of a chromo-
5. Ocular albinism some that results in the loss of a number of genes
E. Color vision defects individually cause specific phenotypes.
Deletion mapping - assignment of a gene to a map
1. Pigment genes
location in the genome after identifying a deletion
2. Blue cone monochromacy
of the chromosome at that location.
3. Rod monochromacy
Digenic inheritance - a pattern of inheritance in a
F. Retinitis pigmentosa
family with mutations in two separate, perhaps un-
1. Autosomal dominant RP linked genes.
2. Autosomal recessive RP Domain - in a protein that results in a particular
3. X-linked RP function.
4. Digenic RP
5. Usher syndrome Dominant negative - deleterious allele which pro-
6. Leber congenital amaurosis duces a more severe phenotype than a null allele at
7. Retinitis punctata albescens the same locus (i.e., interferes with function of the
8. Congenital stationary night blindness other normal allele.
9. Oguchi disease Exon - a sequence of nucleotides that represents part
10. Choroideremia of the final mRNA that is translated into the func-
G. Macular Dystrophy tional protein.

1. Sorsby fundus dystrophy Frameshift - a mutation that shifts the sequence of

2. Stargardt macular dystrophy codons and results in an altered amino acid sequence.
3. Best vitelliform macular dystrophy Genome - the sum total of heritable elements of a cell.
196 Surv Ophthalmol 49 (2) March–April 2004
Genomic DNA - the total DNA including coding and
non-coding sequences.
Haploinsufficiency - the loss of one allele at a ge-
netic locus.
Heterozygous - having two allelic variants of a
gene.
Homeobox - a conserved sequence of DNA with ho-
mology to the homeotic genes in D. melanogaster in-
volved in development.
Homeodomain - a DNA-binding domain within a ho-
meotic gene (see also homeobox).
Homologous - having similar DNA sequence.
Homologous recombination - exchange of chromo-
somal material within regions of similar sequence.
Homologue - chromosomes with identical genetic
loci.
Intron - a sequence of DNA between exons, some-
times referred to as an intervening sequence.
Karyotype - the specific chromosomal complement
of an individual.
Linkage - the association of genetic traits due to their
localization within the same chromosome.
Locus - a specific site within a chromosome.
LOD score - logarithm of the odds of linkage.
Maternal (paternal)isodisomy - a type of uniparental
disomy in which both copies of a maternal (or pater-
nal chromosome are the same).
Missense mutation - a single nucleotide change
that results in a changed single amino acid in a
protein.
Meiosis - the process by which chromosomes are re-
duced in number and distributed into sexual repro-
duction.
MACDONALD ET AL
Mosaicism - two or more cell lines that differ in their
genetic make-up (sometimes chromosome number).
Non-allelic heterogeneity - variation not simply based
on alleles of a single gene, but possibly multiple genes
that cause a similar phenotype.
Orthologue - a sequence of a gene that has diverged
during speciation having possibly the same function.
Penetrance - whether or not a trait is observed in a
patient (e.g., cataract absent or present).
Phenotype - the observed characteristics of a gene or
allele in an individual.
Point mutation - the substitution of a single base pair.
Positional cloning - linking known sequences of DNA
to map the location of a disease gene.
Promoter - a region of DNA involved in the initiation
of transcription of a gene.
Restriction fragment length polymorphism - the se-
quence variation between chromosomes that results
in heritable size fragments of DNA.
Restriction site - the specific palindromic sequence
of DNA that is recognized and cleaved by a restric-
tion endonuclease.
Robertsonian translocation - the fusion of two acro-
centric chromosomes to result in a metacentric
chromosome with the loss of chromosomal material
from the p-arms (short arms) of the acrocentric chro-
mosomes.
Southern blot - the transfer of genomic DNA to a
nylon membrane and probing with radiolabeled
DNA.
Trinucelotide microsatellite marker - heritable re-
peated trinucleotide elements in the DNA that are
used in mapping studies.