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Pathophysiology – EXAM IV

An exam IV survival guide, hope this helps. (*) indicates it will be covered in Monday’s lecture,
so the material I used came from the notes as is.

Rock on,
-Pat Clements


- autosomal dominant trait
- most adults are heterozygotes (homozygotes don’t survive)
- gain of function mutation in fibroblast growth factor receptor 3 (FGFR3)
 arginine substitution (i.e. for glycine)
 abnormal endochondral ossification
- dwarfism with disproportionate arms and legs
- abnormal pelvis, neuro and cardiopulmonary problems, hearing loss, spine deform
- somatotrophin (synthetic human growth hormone) can treat, in early years

- lack of pigmentation
- defect is autosomal recessive
- defect in tyrosinase gene (catalyzes the reactions necessary to make dark pigment)
- heterozygous has normal phenotype, must be homozygous aa to have condition.
Angleman’s syndrome (aka Happy Puppet Syndrome)
- most patients have deletion in the AS region of maternal chromosome 15
- some have paternal uniparental disomy for chromosome 15
- few (3%) have defect in maternal imprinting
- candidate gene: UBE3A - transfers ubiquitin to protein
- targets protein for breakdown by proteasome
- characterized by mental retardation, speech impairment, excitability, inapprop. laughter
- unsteady gait and unsteady limbs

Anhidrotic extodermal dysplasia

- mosaicism, resulting from incomplete X-inactivation in females
- mutant X chromosome gene  lack sweat glands
- use electrochemical resistance test to find areas of skin that are mutant

- caused by a PAX6 mutation
- absence of the iris

Ataxia Telangiectasia
- a disease of DNA repair (nothing else mentioned in lecture)

Becker Muscular Dystrophy (see DMD)

Bloom’s syndrome
- defect in BLM helicase (but other helicases not affected)
 helicase works to unwind tetraplex DNA structures
- leads to chromosomal and genetic instability
Causes: Growth retardation Sunlight sensitivity
Decreased fertility Immunodeficiency
Cancer (both solid tumors and leukemias)

Bruton’s agammaglobulinemia
- defective tyrosine kinase  defective maturation of B-cells
 no Ig production  bacterial infection susceptibility at 4-8 months
(initially ok, b/c antibodies from mother’s breastmilk)
Campomelic dysplasia
- mutant SOX9 gene (homologies to SRY, sex determining region of Y chromosome)
- underdeveloped thorax, bent limbs
- sex reversal (i.e. female with XY karyotype)

Chronic atrophic gastritis – see pernicious anemia

Complete Androgen Insensitivity Syndrome (Testicular Feminization)

- XY female
- has testicular tissue (secretes androgens
- but defective androgen receptor  androgen insensitive
- phenotypically normal female, with some abnormalities

Congenital Adrenal Hyperplasia

- defect. adrenal cortex  overproduction of androgens  virilization of female infants
- often caused by deficiency 21 hydroxylase

- caused by Fibroblast growth factor response genes (cell division/migrat/diff.)
- mutant FGFR 2
- irregular shape of skull
- i.e. Crouzon syndrome and Apert syndrome

Cri du Chat syndrome

- caused by deletion of the p region of chromosome 5
- classified as a contiguous gene syndrome (segmental aneusomy syndrome)
- characteristic “cat cry” in newborns, caused by a pharyngeal defect
- the following webpage has a link to hear what the cry sounds like, and other info
* Cystic Fibrosis
- autosomal recessive disorder (“horizontal” inheritance, heterozygotes not affected)
- single gene mutation, involving a 3 BP deletion (therefore in frame), Δ508 common
- mutant cystic fibrosis transmembrane regulator gene (CFTR)
- abnormal regulation of chloride ion passage through endothelial cells
- In skin, CFTR normally keeps Cl- ions out of sweat ducts
- mutant increased NaCl in sweat  “salty sweat” diagnosis
- In endoth. cells lining airways, Cl- not transported out of cells
 Na rushes in, followed by water  highly dehydrated mucus
- causes lower airway inflammation and infection, chronic breathing difficulties
- GI reabsorption problems, diabetes mellitus, defective pancreatic secretion, cirrhosis
- azoospermia, lack of vas deferens in men
- also decreased fertility in women
- average survival age of 33 yrs.
- more common in Caucasians
- no good molecular test for CF

DiGeorge anomaly of brachial arch defects (related to the other DiGeorge stuff below???)
- defect in thymus development (site of T-cell differentiation and selection)
 leads to T-cell deficiency
 susceptible to yeast and viral infections

DiGeorge Velocardiofacial syndrome

- actually a combo of 3 sydromes: DiGeorge Syndrome (DGS)
Conotruncal anomalies face (CTAF)
Velocardiofacial syndrome (VCFS)
- deletion in DiGeorge Syndrome critical region (DSCR) – [chromosome 22]

- Cardiac problems are the most life threatening

- also cognitive impairments and neonatal hypocalcemia

Down syndrome – see trisomy 21

* Duchene muscular dystrophy (DMD)
- x-linked recessive trait
- apparent non-carrier mother might produce offspring with germline mosaics
- increased risk of child passing on to their progeny
- carrier females are normal
- mutation in the dystrophin gene at Xp21
- the largest human gene
- most common mutation is deletion, though duplication or bad splicing also poss.
- frameshift mutation  absent protein
- dystrophin mainly found in skeletal, heart, smooth muscle tissue
- interfaces between cytoskeletal proteins and group transmembrane proteins
- protein helps maintain muscle calcium permeability
- also acts as shock absorber (prevents damage when fibers contract)

- characterized by progressive myopathy (muscle wasting), starting at age 3-5

- death at age 20-25 from respiratory failure
* Becker muscular dystrophy (BMD)
- less severe progressive myopathy than DMD, less common than DMD
- truncating mutations at Xp21
- in-frame mutation  partially functioning dystrophin protein
- typically later onset than DMD
- Molecular Testing:
- Immunofluorescence staining for dystrophin protein in muscle sample
- PCR amplification of gene

Edward’s syndrome – see trisomy 18

- environmental factors can influence genes
- α1-anti-trypsin, coded by the Serpina genes (multiple alleles)
-blocks degradation of proteins (inhibits trypsin and elastase)
- smoking introduces superoxide anion  inhibits this enzyme  can’t protect
 breakdown of structural proteins  emphysema

Faconi Anemia
- bone marrow failure, growth retardation
- skin, G.I., and kidney abnormalities
- increased cancer occurrences, particularly myolegnous leukemia
- increased chromosome damage (more susceptible)
- defect in a Faconi complementation group
 possibly knocks out important signal or repair pathway
* Factor V Leiden Trhombophilia
- single point mutation in factor V gene at nucleotide 1691
- G A base substitution leads to Arginine  to histidine
- occurs at an APC cleavage site (therefore Activated Protein C resistance)
- causes slower inactivation of Factor V by APC
 increases thrombin production
- increased risk of clotting (thrombosis)
- heterozygotes have slightly elevated risk
- detect mutation by MnI 1 enzyme digestion
(mutants have one less cleavage site, so produces 2 DNA fragments instead of 3)

Fetal Alcohol syndrome

- teratogen = ethanol
- causes low birthweight, growth delay, heart defects

Fetal Dilantin syndrome

- teratogen – dilantin (anti-epileptic drug)
- causes hypertelorism, short nose and low nasal bridge

- example of ecogenetics
- decreased activity in glucose-6-phosphate dehydrogenase
 less reduced glutathione  oxid. damage to RBC’s
- oxidant drugs can accelerate loss of glutathione
- or ingestion of fava beans
- So is it just me, or does half of what we learned in block 1
relate to Silence of the Lambs?

Folate deficiency - see homocysteinemia, neural tube defects, megaloblastic anemia

Fragile X syndrome
- classified as a DNA repeat expansion disorder, loss of function
- most common inherited form of mental retardation (remember, trisomy 21 is common,
yet it is not caused by the inheritance of a specific gene, but rather by having an extra
whole chromosome)
- some have mild facial dysmorphic features, while others have no symptoms at all
- self-injurious, hyperactive, and impulsive behaviors most common
- fragile site contains a CGG sequence, repeated in the 5’ region of FMR1 gene
- repeat occurs upstream of the start codon
- FMR1 encodes an RNA binding protein that interacts with polyribosomes
- with disease, characteristic low expression in brain and testes
- more repeats  greater inactivation (b/c highly unstable during mitosis)
(6-50 repeats is normal, 50-200 is permutation, 200+ is full mutation)
- repeats due to uneven crossing over or amplification b/c of defect replication
- repeats accumulate over generations
- to test for fragile X, run PCR of FMR gene, then separate using electrophoresis
- look for large DNA sequence (won’t move far in the gel)

- autosomal recessive, equal gender and race ratios
- can’t metabolize galactose (serum levels higher than 3-4 mg/dl)
- defective galactokinase or uridine diphosphate hexose-4-epimerase
- Most common – defect galactose-1-phosphate uridyltransferase
- can’t convert to UDP-galactose and glucose-1-P
- severity depends on type of variant
- buildup of galactisol (toxic)
- causes cataracts, jaundice, liver enlargement
- TREAT: - restrict galactose in diet (i.e. milk)

- defective purine metabolism  excess uric acid
- Sodium urate crystal deposits in joints  painful attacks, often in toes
- multiple possible causes:
- defective PRPP synthase  can’t be regulated  oversynth of purines 
therefore many broken down)
- defective glucose-6-phosphatase  increased G6P  inc Ribose 5-P via PPP
 therefore oversynthesis of purines
- partial HGPRTase deficiency  can’t salvage purines properly  inc uric acid

(Gout is not actually caused by the evil gout demon with the
stingray barb tail)
- Follow this link for an 18th century newspaper editorial
regarding the treatment of gout
Hand-foot-genital syndrome
- caused by HOX-A13 mutation
- just like it sounds, defects in the hands, feet, and genitals

* Hereditary Hemochromatosis
- iron overload disorder (transferrin saturation, increased serum ferritin)
- autosomal recessive trait, but phenotype is sex-influenced
- less common in females
(possibly b/c of less dietary iron uptake and losses via menstruation)
- molecular testing on HFE gene (common: C282Y and H63D mutations)
- HFE facilitates transferrin-bound iron uptake from gut
- if mutant, cell fails to sense circulating T.F.-bound iron
 increased absorption of dietary iron
 high expression of iron transporters, but low ferritin expression
- heterozygotes have elevated serum iron, but no major iron overload complications
- takes long time to develop pathology
- especially toxic to liver and kidneys

Hemophilia A
- X-linked recessive
- higher incidence in males (since hemizygous)
- deficient in factor VIII (clotting factor)
- traced in royal families of Europe

Hereditary Orotic Anemia

- caused by two deficiencies:  can’t make pyrimidines
- orotidine-5-P phosphorylase
- orotidine-5-P decarboxylase
- leads to decreased UTP (inhibitor of the pathway)
 high flux through  increased orotic acid
-Treatment: uridine
(+ kinase)  UMP  UDP  UTP synthesis  can downregulate pathway

Hermaphroditism (2 classifications)
PSUEDO: - XX male w/ gonadal dysgenesis (can’t undergo puberty)
- SRY factor was transferred to X chromosome
TRUE: - 46, XX
- has both testicular and ovarian tissue, both sex organs, or ambiguous
Heterogeneous Nonpolyposis Colon Cancer
- a disease of DNA repair (nothing else mentioned in lecture)

HIV (Human Immunodeficiency Virus)

- great variety among viruses b/c lacks reverse transcriptase 3’-5’ exonuclease activity
- polycistronic nuclear material, RNA spliced after transcription
 target for protease inhibitors!

- autosomal recessive
- homocysteine is produced from methionine.
- Classical Homocystinuria - defect serine cystathione synthase (chromosome 21)
- can’t covert homocysteine  cystathione
- also disease with B12 deficiency
- can’t re-methylate homocyteine to form methionine
- Methionine synthase deficiency
- converta homocysteine to methionine (requires methyl-THF cofactor)
- blocks the reconversion of methyl-THF  THF
- Characterized by developmental delay, childhood osteoporosis, myopia & ectopia lentis
- increased CHD (increased thrombus risk)
- TREAT with folic acid, pyroxidine
- restrict methionine in diet, and supplement cysteine.

Huntington’s Disease
- single gene mutation
- classified as a DNA repeat expansion disorder
- autosomal dominant (“vertical” inheritance, heterozygotes are affected)
- expansion of CAG repeat in the coding region for the protein Huntingtin
 causes a polyglutaminyl chain to be added (gain of function)
- extra glutamines causes Huntingtin aggregation in brain cell nuclei
- binds to Huntingtin associated protein (HAP) in brain
- later onset, usually well into reproductive age (30-50 years old)
- all heterozygotes will eventually express phenotype
- 50% express it by age 50
- chorea (abnormal voluntary movement)
- dementia (basal ganglia atrophy and dilation of lateral ventricle)
(degredation in cerebral cortex and basal ganglia)
- autosomal recessive, equal gender ratios
- disorder of urea cycle, many enzyme deficiencies possible
- most common – deficient ornithine transcarbamylase
- can’t convert carbamoyl phosphate  citrilline, for shuttle out of mitochondria
- anorexia, hypothermia, edema, respiratory problems, tremors, poor coordination
- TREAT: - stop protein uptake
- supplement non-protein calories
- dialysis

- autosomal recessive (equal gender ratios, but racial differences exist)
- generally classified with serum phenylalanine higher than 2mg/dl
- Classical Phenylketonuria Hyperphenylalaninemia (most common)
- caused by lack of phenyalanine-4-hydroxylase [PAH] (can’t catabolize)
- allelic heterogeneity allows for different levels of enzyme (different severities)
- Non-classical PKU (BH4 deficiency hyperphenylalaninemia)
- deficiency in tetrahydrobiopterin (BH4)
- this is a necessary cofactor for PAH
Hyperphenylalaninemia characterized by:
- increased serum phenylalanine
- decreased tyrosine, melanin, fumarate, and catecholamines
- irritability, eczema-like rash, musty urine odor
- microcephaly, mental retardation
- TREAT: - supplement BH4 and tyrosine
- avoid high protein foods
- high carbs and fats instead for energy

- defective purine metabolism
- leads to increased uric acid in blood and urine

Human Heavy Chain Diseases (HCDs)

- disorder of B cells, producing Ig’s without light chains
- result of improper gene rearrangments

Kearns-Sayre syndrome
- caused by deletions in mitochondrial DNA (mtDNA)
- multisystem disorder, mainly brain and muscle dysfunction (can’t do OXPHOS)
- also short stature, hearing loss, mental retardation
Klinefelter syndrome
- 47, XXY (aneuploidy)
- longer arms and legs
- imbalanced sexual development
- underdeveloped genetials
- infertility
- abnormal breast development (gynecomastia)
- fat distribution in body similar to females

Lesch-Nyhan Syndrome
- absence of HGPRT (hypoxanthine-guanine phosphoribosyl transferase)
- hyperuricemia (2 ways)
 increased PRPP  increased purine synthesis  increased uric acid
 decreased GMP  increased purine synthesis
- since brain is reliant on salvage pathway  neurological effects
- self-mutilation, mental retardation, etc

Marfan Syndrome
- autosomal dominant (“vertical” inheritance, heterozygotes are affected)
- mutant glycoprotein fibrillin-1 gene (FBN1)
 can’t properly synthesize elastic connective tissue
 ruptured aorta, skeletal manifestations, dislocated lenses
- variable expression in humans (different phenotypes in everybody)
Maternal Diabetes
- teratogenic
- causes large birthweight, brain anomalies, heart defects

Medium chain acyl CoA dehydrogenase (MCAD) deficiency

- autosomal recessive
- β-oxidation disorder
- defective carnitine uptake (therefore shuttle in medium chain F.A. [6-12 carb])
- observed in infants after fasting 4+ hours (increased β-oxidation)
- causes sever hypoglycemia and hypoketonuria (b/c can’t make energy from fats)
- accumulate monocaroxy fatty acids and dicarb. fatty acids
- attempt to break these down with w-oxidation (byproducts in urine)
- disabled gluconeogenesis (b/c no free acetyl coA)
- accumulate octanoic acid (8C) – toxic to mitochondria
- causes lethargy, coma, enlarged liver
- TREAT: - carnitine
- low fat diet, instead use high carb and protein

Megaloblastic Anemia
- abnormally large RBC precursors (megaloblasts)
 abnormally large RBC’s (macrocytic)
- insufficient nucleotide synthesis in rapidly dividing cells
- either folate or B12 deficiency (pernicious anemia)
- important to find out though, b/c B12 deficiencies have other effects too
i.e. demylenation of neurons (Folate defic. can mask B12 defic.)
- find out using serum folate, B12, and methylmalonic acid levels

- has been targeted with gene therapy (experiemental)
- removed T cells from body (therefore ex vivo)
- insert gene for specific T-cell receptor (TCR), inject cells into patient
 t-cells can recognize and trigger immune response against melanoma

- autosomal recessive lysosomal storage disease
- can’t degrade mucopolysaccharides
- Sanfilippo syndrome most common, 4 subtypes
- hydrocephalus, angina, obstructive airway disease, ophthalmologic, musc/skel disease
- many die early in life
- TREAT: bone marrow transplant can help with some of the effects, prolong life
Myotonic dystrophy
- a DNA repeat disorder
- CTG repeat occurs after the stop codon

Neurofibromatosis Type I
- autosomal dominant
- mutant NF1 gene
 decrease in neurofibromin (a tumor suppressor protein)
- nuerofibromas
- abnormally dilated blood vessels, stenosis, hypertension, aneurisms, optic nerve gliomas

Neural tube defects

- arise in early fetal development, either from folate of B12 deficiency
- possible insufficient nucleotide synthesis in rapidly dividing cells
- reduced in number since folate supplementation began (i.e. bread)

Non-Syndromic Deafness
- example of locus heterogeneity
- mutations on different loci (therefore different genetic causes)
 all can lead to deafness (different genotype  same phenotype)

Noonan Syndrome
- similar to Turner syndrome, but has a normal karyotype
- both sporatic and autosomal dominant cases have been observed
- mutant protein tyrosine phosphatase non-receptor type II (PTPN11)
 gain of function? (pathophys not completely understood)
- facial irregularities, most dangerous is the congenital heart disease

Osteogenesis Imperfecta
- dominant negative mutation
- defective type I collagen (made of 2 α-1 chains and 1 β-2 chain)
- α-1 (COL1A1 gene)
- β-2 (COL1A2 gene)
- T1 collagen is major struct. component of bone/fibrous tissue
- mild type (I)  decreased production of collagen, but normal chains
- more severe types (II, III, IV)  missense mutation = amino acid change
 abnormal collagen
- brittle bone disease, also shortened and bowed femur
- presents as multiple current/healed fractures
- Molecular Testing: - analysis of collagen
- mutation analysis
Patau syndrome – see trisomy 13

Pearson’s Syndrome
- caused by mitochondrial DNA (mtDNA) deletion
- non-neurological childhood pancytopenia (low RBC’s and WBC’s) and pancreatic dys.
- if survival to childhood, becomes Kearns-Sayre syndrome

Pernicious anemia
- caused by decreased intrinsic factor  can’t absorb B12
- causes deterioration of stomach lining
 Chronic atrophic gastritis (an autoimmune disorder)
- can be cured with monthly B12 injections

Phenylketonuria (PKU) – see hyperphenylalaninemia

- rare genetic disorder
- causes severe shortening of the arms and legs
- the toxic effects of thalidomide prenatally are considered a phenocopy of phocomelia

Prader-Willi Syndrome (PWS)

- most patients have deletion of PWS/AS region of paternal chromosome 15
- some have maternal uniparental disomy for chromosome 15
- few (5%) have mutation in the gene that controls paternal imprinting (still biparental)
- candidate gene: SNRPN - encodes SmN protein associated w/ snRNP’s
- involved in pre-mRNA processing
- characterized by severe hypotonia, obesity (insatiable appetite)
- short stature, small hands and feet, hypogonadism
- mental retardation, stubbornness, controlling/manipulative behavior (bring in Dr. Phil!)

Purine Nucleoside Phosphorylase Deficiency

- leads to a buildup of dGTP  inhibits ribonucleotide reductase  dec. DNA synthesis
- deficiency of T cells, but B cells are fine

Retinoic Acid Embryopathy

- teratogenic
- causes cranialfacial defects, heart/limb defects, severe developmental delay
Sanfilippo syndrome – see mucopolysaccharidoses

Severe Combined Immunodeficiency Syndrome (SCIDS)

- deficient adenosine deaminase [ADA] (catalyzes deamination of adenosine to inosine)
 buildup of dATP  inhibits ribonucleotide reductase
 therefore inhibits DNA synthesis
- disease has deficiency in both B and T cells  NO immune system
- could also be caused by defect in Ig or TCR (no effective immune system)
- like defective RAG genes (improper recombination)
- X-linked form = mutation in IL-2 receptor gene γ subunit
- “bubble boy”
- possible treatment involves ingestion of ADA enzyme in a polyethylene
glycol tablet (PEG-ADA), or gene therapy w/ retrovirus

Situs Inversus
- caused by mutant ZIC3 gene (zinc-finger gene)
- abnormal left/right organ alignment in body

Skeletal dysplasia
- caused by Fibroblast growth factor response genes (cell division/migrat/diff.)
- mutant FGFR 3
- i.e. Achondroplasia (see for more info)

- caused by a HOX-D13 mutation
- bony fusions and accessory bones in hands and feet

- frameshift mutation (4 BP insertion)
- neurologic degeneration, blindness, deaf, paralysis, death by 3 yr
- defect β-N-acetylhexosaminidase (Hexosaminidase A)
 gangliosides with GalNAc cannot be degraded
 lipid deposits form in neurons

Telomerase (in aging and cancer)

- activity of telomerase decreases with aging (serves a counting mechanism)
 chromosome ends degrade  cell division stops
- increased activity in 85% - 90% of human tumors
 turns off “counting”  cells divide more than they should  cancer
- therefore, telomerases would be good targets for antineoplastic drugs
- 4N chromosome number (92)
- either XXXX or XXYY
- caused by failure to complete cleavage in early zygote cell division
(genetic material duplicates, but cell doesn’t actually divide)

- group of hereditary anemias, caused by defective globin chain synthesis (α/β)
- possible genetic causes: - defect mRNA processing (intron mutations)
i.e. sickle cell
- nonsense mutations (termination codon added)
- termination code mutations
- α-thalassemia is an example of modifying loci (gene modifies other gene)
- leads to decreased severity of sickle cell disorder
(less Hb  decreased amount to polymerize and change cell shape)

Thalidomide embryopathy
- phocomelia and heart/ear anomalies

- 3N, having an extra sex chromosome (XXX or XXY)
- lethal, early spontaneous abortion
- trunk:head disproportion and syndactyly (fused fingers)
- Causes: - 2nd polar body doesn’t eject from egg [diagyny]
- fertilization by two sperm (improper polyspermy block) [diandry]
- nondisjunction in meiosis I/II
- nondisjunction in mitosis (cleavage furrow before complete separation)
Diandry: - extra paternal set (contributes more to membranes and placenta)
- huge placenta, larger than fetus (partial hydatidiform mole)
Diagyny: - [think gyn = woman]
- extra maternal set (contributes more to embryo proper)
- small placenta, normal fetus development with enlarged head

Trisomy 13 (Patau syndrome)

- if babies come term, often die within the first year
- polydactyl (extra fingers)
- cleft lip and palate
- lower set ears (don’t fully shift up to normal position during development)
- microencephaly and mental retardation
- Holoprosencephaly – incomplete midline differentiation in head
(combined single eye or eyes too close, defects in nose and mouth)
Trisomy 18 (Edward’s syndrome)
- if babies come term, often die within the first year
- mental retardation
- short neck, lower set ears
- characteristic clenched fist (can be visualized with ultrasound)

Trisomy 21 (Down Syndrome)

- 3 copies of chromosome 21 (therefore 47, XY (or XX) +21)
- mental retardation, flat nose, close-set eyes w/ slanting eyelids, protruding tongue
- likelihood related to maternal age
- 85% of cases maternal derived
- An estimated 1.5 fold increase in expression of genes on chromosome 21, including an important
peroxide mutase enzyme. This has been implicated in both having enhanced protective effects on
individuals with down syndrome (cardioprotective, anti-cancer), but could disrupt the free O2 balance,
possibly leading to Alzheimer’s.

Turner syndrome
- 45, X (aneuploidy)
- often spontaneously aborted due to fluid imbalance
- severe lymphedema (lymphatic blockage)
- cystic hygroma (fluid filled sac in the back of the head)

UV Light Damage
- causes pryimidine dimer (thymine)
- thymines can be reversed with photolyase (breaking cyclobutane ring of the dimer)
- enzyme activated by UV light exposure (smart )

Waardenburg Syndrome
- autosomal dominant, loss of function mutation
- “vertical” inheritance, heterozygotes are affected
- defect in HuP2 (PAX3) homeobox gene ( TF)
- causes white forelock, premature graying,
different colored eyes, deafness

Rogue from X-men???

Werner’s syndrome
- defective WRN helicase
- this helicase may be involved with recombination
- chromosomal and genetic instability
- causes excessive aging
 cardiovascular disease, arthritis, cancer
William’s Syndrome
- rare, deletion involving elastin gene (ELN)
- cardiovascular problems (i.e. supravalvular arotic stenosis)
- connective tissue problems, hypercalcemia, distinct facial features

- Deficiency is xanthine oxidase (converts xanthine  uric acid)
- increased excretion of xanthine and hypoxanthine
- decreased uric acid production
- causes kidney stones (xanthine lithiasis)

X-linked dominant hypophosphatemia (aka Vitamin D deficient Rickets)

- in pedigrees, more evident in females than males
- heterozygotes are affected
- defect PHEX
(phosphate-regulating gene with homologies to endopeptidases on the X chromosome)
- low blood phosphate levels, high urinary phosphate levels
- short stature, bone defects as seen in classic rickets

Xeroderma Pigmentosum
- autosomal recessive
- growth and neurological defects
-extreme sensitivity to light
- defect in excision repair
- protein XPA binds to damaged site
 complex unwinds DNA
 30 nucleotide sequence removed and repaired
- since such a large chunk removed for repair,
higher likelihood of error
- increased cancer occurrence


Wasn’t that fun?