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Summary
In the last 18 years the genes that encode all but one of the 29
blood group systems present on red blood cells (RBCs) have
been identified. This body of knowledge has permitted the
application of molecular techniques to characterize the common blood group antigens and to elucidate the background for
some of the variant phenotypes. Just as the RBC was used as a
model for the biochemical characterization of cell membranes,
so the genes encoding blood groups provide a readily accessible
model for the study of gene expression and diversity. The
application of genotyping techniques to identify fetuses at risk
of haemolytic disease of the newborn is now the standard of
care, and the expansion of nucleic acid testing platforms to
include both disease testing and blood typing in the blood
centre is on the horizon. This review summarizes the
molecular basis of blood groups and illustrates the mechanisms
that generate diversity through specific examples.
Keywords: blood group, allele, molecular techniques, genotyping, genetic diversity.
For well over a century, blood group antigens have been
recognized as differences between the red blood cells (RBCs) of
one person and another. Antigens have been defined by human
antibodies, immune and naturally occurring, as well as those
deliberately stimulated in animals. Assignment of blood group
antigen status requires the novel factor to be inherited from
one generation to the next, thus demonstrating that blood
group antigens were the products of genes. Many of the
cellular components that carry blood group antigens have been
identified and characterized and indeed, the RBC has provided
a useful model for the study of cell membranes. Concurrently,
the genes encoding the blood group proteins have been
mapped to different chromosomes throughout the genome.
The development of DNA sequencing techniques, and then the
polymerase chain reaction (PCR) has paved the way for the
rapid molecular characterization of the genes encoding blood
group antigens, such that, in the last 18 years, all but one of
the 29 blood group genes have been characterized. This
doi:10.1111/j.1365-2141.2004.05065.x
760
CO
LW
CH/RG
H
XK
GE
1
2
3
4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
ABO
MNS
P
Rh
Lutheran
Kell
Lewis
Duffy
Kidd
Diego
Yt
Xg
Scianna
Dombrock
Colton
LandsteinerWiener
ChidoRodgers
Hh
Kx
Gerbich
Cromer
Knops
Indian
KN
IN
CROM
SC
DO
YT
XG
KEL
LE
FY
JK
DI
LU
P1
RH
ABO
MNS
ISBT
number
ISBT
Name
ISBT
system
symbol
1q32
11p13
1q32
19q133
Xp211
2q14-q21
6p213
7p14
19p132-cen
1p34
12p132-p121
7q22
Xp2232
7q33
19p133
1q21-q25
18q11-q12
17q12-q21
19q132
22q112-ter
1p3613-p343
9q342
4q282- q311
Chromosome
location
CR1
CD44
DAF
C4A
C4B
FUT1
XK
GYPC
AQP1
ICAM4
ERMAP
ART4
ACHE
XG
KEL
FUT3
DARC
SLC14A1
SLC4A1
LU
ABO
GYPA
GYPB
P1
RHD
RHCE
ISGN
gene
symbol
NM_000573
NM_000610
NM_000574
NM_007293
NM_000592
NM_000148
NM_021083
NM_002101
NM_000385
NM_022377
NM_018538
NM_021071
NM_015831
NM_175569
NM_000420
NM_000149
NM_002036
NM_015865
NM_000342
NM_005581
NM_020469
NM_002099
NM_002100
NM_016225
NM_138618
Genbank
account
number*
a3GalNAcT, a3GalT
Glycophorin A
Glycophorin B
a4GalT?
RhD
RhCE
CR1
Hermes antigen
ERMAP (IgSF)
ADP-ribosyltransferase 4
Dombrock glycoprotein
CHIP, Aquaporin-1
ICAM-4
LW glycoprotein (IgSF)
Complement factor 4A
Complement factor 4B
a2FucT
Xk glycoprotein
GPC
GPD
DAF
Acetylcholinesterase
Xg glycoprotein
I
I
S
S
II
M-10
I
I
GPI
M-6
I
I
GPI
GPI
I
I
I
II
II
M-7
M-10
M-14
II
I
I
M-12
M-12
Gene product
Protein
type
Table I. Summary of information on genes and gene products in the currently acknowledged blood group systems.
170280
80
n.a.
37
32
23
70
n.a.
28 or 50
42
60
5457
160
2229
93
n.a.
3545
50
90
7885
n.a.
36
24
n.a.
3032
Apparent
mass
(kDa)
1998
341
1741
1744
365
444
128
107
347
269
241
475
314
557
180
597
557
732
361
338
389
911
354
131
72
417
417
Number
of amino
acids
CD35
CD44
CD173
CD236R
CD236
CD55
CD242
CD99
CD258
CD234
CD233
CD239
CD235a
CD235b
CD240D
CD240CE
CD
number
8
2
12
1
1
7
3
3
4
5
2
2
24
6
6
3
21
19
1
48
4
43
Number of
antigens
Caras et al (1987),
Medof et al (1987)
Wong et al (1989)
Goldstein and Butcher (1990),
Harn et al (1991)
Kelly et al (1994)
Ho et al (1994)
Colin et al (1986)
Yu et al (1986), Yu (1991)
Lee et al (1991)
Kukowska-Latallo et al (1990)
Chaudhuri et al (1993)
Olives et al (1994)
Tanner et al (1988),
Lux et al (1989)
Li et al (1991)
Darling et al (1986),
Ellis et al (1994)
Ye et al (2000)
Gubin et al (2000)
Yamamoto et al (1990b))
Siebert and Fukuda (1986)
Siebert and Fukuda (1987)
Avent et al (1990),
Cherif-Zahar et al (1990),
Le Van Kim et al (1992),
Arce et al (1993),
Kajii et al (1993)
Parsons et al (1995)
Cloning reference
Review
24
25
26
27
28
29
Ok
Raph
JMH
I
Globoside
GIL
OK
RAPH
JMH
I
GLOB
GIL
ISBT
system
symbol
19p133
11p155
15q223-q23
6p24
3q25
9p13
Chromosome
location
BSG
MER2
SEMA7A
GCNT2
B3GALT3**
AQP3
ISGN
gene
symbol
NM_001728
NM_004357
NM_003612
NM_145649
NM_033169
NM_004925
Genbank
account
number*
Neurothelin, basigin
MER2
H-Sema-L
b6GlcNAcT
b3GalNAcT1, P synthase
Aquaporin-3
Gene product
I
M-4
GPI
II
II
M-6
Protein
type
3569
40
7580
n.a.
n.a.
45
Apparent
mass
(kDa)
248
253
656
400
331
292
Number
of amino
acids
CD147
CD151
CD108
CD
number
1
1
1
1
1
1
Number of
antigens
Guo et al (1998)
Hasegawa et al (1996)
Yamada et al (1999)
Bierhuizen et al (1993)
Amado et al (1998)
Inase et al (1995)
Cloning reference
*Several different GenBank entries may exist for each system; n.a., not applicable. Most accession numbers given were retrieved from http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.pl in July
2003.
Type I and II are single membrane pass molecules with their amino- or carboxyterminals outside the cell (inside the Golgi for glycosyltransferases) respectively. M-n is a multimembrane pass molecule
that traverses the membrane n times; GPI is a molecule anchored to the RBC membrane via a glycosylphosphatidylinositol link; S is a molecule that is found in its soluble form in plasma but has been
adsorbed to the RBC membrane and covalently bound to lysine residues.
In some instances the number of amino acids given may vary between different variants/forms of the molecule.
Whilst the primary gene product is the glycosyltransferase given, the blood group antigens are carried by carbohydrate structures on glycoproteins and/or glycolipids.
The size given corresponds to the full length of C4. Observe that the C4d fragment only is adsorbed and bound to the RBC and carries the CH/RG antigens.
**Current gene name based on the erroneous assignment of the gene product as a b3-galactosyltransferase.
ISBT
number
ISBT
Name
Table 1. (continued)
Review
761
Review
Table II. Single nucleotide polymorphisms (SNPs) associated with selected antigens in some important blood group systems.
System symbol
Antigen 1
Antigen 2
Reference
ABO
MNS
A
M
S
C
E
Lua
Aua
K1
Kpa
Fya
B
N
s
c
e
Lub
Aub
K2
Kpb
Fyb
Jka
Dia
Wra
Yta
Sc1
Doa
Coa
LWa
Tca
Ina
G838A Asp280Asn
C2561T (Leu854Pro)
G1972A Glu658Lys
C1057A (His353Asn)
G169A (Gly57Arg)
A793G (Asn265Asp)
C134T (Ala45Val)
A308G (Gln70Arg)
G155T (Arg18Leu)
C252G (Pro46Arg)
Jkb
Dib
Wrb
Ytb
Sc2
Dob
Cob
LWb
Tcb
Inb
Yamamoto et al (1990a)
Siebert and Fukuda (1986)
Siebert and Fukuda (1987)
Mouro et al (1993), Simsek et al (1994)
Mouro et al (1993), Simsek et al (1994)
El Nemer et al (1997), Parsons et al (1997)
Parsons et al (1997)
Lee et al (1995)
Lee et al (1996)
Chaudhuri et al (1995), Iwamoto et al (1995),
Mallinson et al (1995), Tournamille et al (1995b)
Olives et al (1997)
Bruce et al (1994)
Bruce et al (1995)
Bartels et al (1993)
Wagner et al (2003)
Gubin et al (2000)
Smith et al (1994)
Hermand et al (1995)
Lublin et al (2000)
Telen et al (1996)
RH
LU
KEL
FY
JK
DI
YT
SC
DO
CO
LW
CROM
IN
*Additional missense mutations that differ between these alleles can occur.
Another missense mutation at this position encodes a blood group antigen of very low prevalence that is antithetical to antigen 1 and antigen 2.
Review
Table III. Molecular mechanisms that generate diversity in blood group genes.
Type of change
Molecular mechanism
Phenotypic consequence
Antithetical antigen
Novel antigen
Missense SNP
Missense SNP
Equal crossover between homologous genes
DNA conversion between homologous genes
Exon duplication
Missense SNP
KEL 698C>T
GYPB161G>A
GYP(B-A)
RH(D-CE-D)
GYPC.Lsa
ABO646T>A
FY 298C>T
CROM 596C>T
GYPB intron 5 +5g>t
XK intron 2 +5g>a
K2K1 antigen
Mit+
Ss+wU, Dantu+
DVI, BARC+
Ls(a+)
Ax
Fyx
Dr(a)
SsU+w
McLeod phenotype:
weakened Kell antigens
Gy(a)
Rhnull
Co(ab)
Fy(ab)
Gy(a)
D
En(a)
Lu(ab)
Reduced amount of
expected antigen
No protein product
Non-sense SNP
Nucleotide deletion
DO 442T>C
RHAG 1086delA
CO 232delG
FY 46T>C
DO intron 1 2a>g
DRHD
DGYPA
In(LU)
763
Review
Fig 1. Hybrid genes arising from crossover events between ABO genes have been shown to give rise to more or less unexpected phenotypes. In this
example, a crossover in intron 6 between an O1v allele and a B allele to generate a BO1v hybrid was shown to be one molecular mechanism behind the
Ax phenotype (Olsson & Chester, 1998). Weak A antigen expression occurs because exon 7 of the O1v allele encodes A transferase activity that is
normally silenced by the presence of 261delG in exon 6. Since exon 6 is derived from the B allele without this deletion in the hybrid, enzyme activity is
restored. The corresponding product of the crossover would be expected to encode a non-functional protein since the 261delG mutation is present in
exon 6. Indeed, such an allele was reported to be common in Brazilian blacks (Olsson et al, 1997) and has since been found in Blacks of several
different geographic origins (unpublished observations). Note that the introns are not drawn to scale.
Review
765
Review
Fig 3. A single nucleotide deletion in the coding region of a gene can alter the open reading frame. For example, in the ABO blood group system, the
deletion of 261G in the consensus sequence (A1 allele) results in a frameshift and a subsequent introduction of a premature stop codon (O1 allele).
The truncated protein that is encoded is inactive. Conversely, the A2 allele results from the deletion of 1061C, and instead, the open reading frame is
elongated. The glycosyltransferase encoded by this gene consists of 21 additional amino acids and is less efficient, as determined by the presence of
fewer A antigens on the RBCs of group A2 people. In addition, it appears to be unable to synthesize the A1 antigen. Asterisks (*) represent stop
codons. The grey shading indicates nucleotides that are transcribed normally; the white boxes indicate a nucleotide sequence that is not transcribed as
a result of the nucleotide deletion at position 261; the hatched box represents the additional nucleotide sequence that is transcribed as a result of the
nucleotide deletion at 1061.
Future perspectives
Today, almost all of the genes underlying expression of the
human blood group systems have been cloned and the
polymorphisms responsible for the phenotypes encountered
in different individuals and populations clarified. A challenge
that remains for the future is to investigate and understand the
genetics of antigens in the blood group collections and series
since our experience tells us that they are likely to be carried on
functional molecules.
The increasing knowledge of the genes encoding blood
group antigens has relevance in the clinical laboratory.
Genomic typing assays for fetal RBC phenotype prediction to
determine the risk to a foetus of haemolytic disease of the
newborn are now standard of care. Much of this testing is
performed on DNA isolated from amniotic fluid; however, in
the last few years, more sensitive quantitative PCR techniques
have permitted the identification of fetal RHD alleles from
DNA isolated from maternal plasma (Lo et al, 1998; Lo, 2001;
Review
van der Schoot et al, 2003). Although there are some current
limitations to the technique, the advantages of this noninvasive method are obvious. Other applications of blood
group genotyping have included testing samples from multiply
transfused patients that are either immunized, or at risk of
being immunized, to one or more blood group antigens (Reid
et al, 2000). Patient groups, such as those with Sickle Cell
Disease or other transfusion-dependent haemoglobinopathies,
can benefit from better antigen-matched blood (Reed &
Vichinsky, 2001). Genotyping is also useful in other serological
situations where the RBC phenotype cannot be accurately
determined (Rios et al, 2000b).
The potential for testing blood donor samples on a large
scale is clear to all in the field, but current techniques are both
laborious and expensive. However, automation of SNP detection, as a faster and easier way to type blood donors, is a
much-discussed issue and there are several techniques being
evaluated.
Lastly, the knowledge gained from the identification of
blood group genes leads to a better understanding of the
relationship between blood group differences and subtle
functional differences in the molecules that carry the antigens.
The molecular genetics of blood groups may also help us to
better understand the functionality of the RBC at large, e.g.
moderation of the intracellular environment for invading
parasites, plasticity of the RBC membrane in the circulation
during stress, or the role of the circulating RBC in haemostasis.
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