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8/9/2019 Genetic Basis of Blood Group Diversity - Storry - 2004 - British Journal of Haematology - Wiley Online Library

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Genetic basis of blood group diversity

Jill R. Storry and Martin L. Olsson

Blood Centre, University Hospital and Department of Transfusion Medicine, Institute of Laboratory Medicine, Lund, Sweden

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 com-

mon 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, geno-

typing, 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

knowledge, combined with continual improvements in gene

analysis are changing the way in which testing can be

performed.

Blood group antigens are part of carbohydrate or protein

structures exposed on the extracellular surface of the RBC

membrane. In blood group nomenclature, antigens encoded by

the same gene, or cluster of genes, are assigned to the same

blood group system. Each system may consist of one or more

antigens. Proteins that are glycosylated by N-linked glycans,

e.g. band 3 also carry carbohydrate antigens, like ABH and I

antigens. Currently, 29 blood group systems, which include a

total of 240 antigens, have been established by the Interna-

tional Society of Blood Transfusion (ISBT) Committee on

Terminology for Red Cell Surface Antigens. In addition, 38

antigens not yet fulfilling the requirements for classification

into a system have been gathered in collections or series of

high- and low-frequency antigens (Daniels et al, 2003). These

numbers are not static and new blood group antigens are

identified by unusual serological findings each year.

This review will discuss the genes and polymorphisms

underlying the expression of human blood group systems. A

comprehensive summary of information detailing the genesand carrier molecule(s) for each blood group system has been

collated in Table I and the single nucleotide polymorphisms

(SNPs) associated with some clinically important antigens are

shown in Table II.

References describing the cloning of the genes and the

identification of the specific polymorphisms are given in the

appropriate table. In addition, a selection of relevant references

is given throughout the text, mostly the ones that serve as

illustrative examples of different genetic principles. Additional

papers describing the elucidation of the polymorphisms

responsible for the blood group antigens within each system

can be retrieved via the GenBank accession numbers given in

Table I and at the Blood Group Antigen Database (http://

www.bioc.aecom.yu.edu/bgmut/index.htm). The interested

reader is also referred to current textbooks and reviews, a

few examples of which can be found in the reference list (Issitt

& Anstee, 1998; Reid & Yazdanbakhsh, 1998; Daniels, 2002;

Reid & Lomas-Francis, 2003).

In general, antigens belonging to blood group systems are

better characterized at the molecular level than those antigens

assigned to a collection or series. In most instances, the paucity

of genetic data regarding the latter antigens prevents assign-

Correspondence: Martin L. Olsson, Blood Centre, University Hospital

and Department of Transfusion Medicine, Institute of Laboratory

Medicine, Lund, Sweden. E-mail: [email protected]

review

2004 Blackwell Publishing Ltd, British Journal of Haematology, 126, 759771 doi:10.1111/j.1365-2141.2004.05065.x


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Table

I.

Summaryofinformationon

genesandgeneproductsinthecurrentlyacknowledgedbloodgroupsystems.

ISBT

Name

ISBT

number

ISBT

system

symbol

Ch

romosome

loc

ation

ISGN

gene

symbol

Genbank

account

number*

Gene

product

Protein

type

Apparent

mass

(kDa)

Number

ofamino

acids

CD

number

Numberof

antigens

Cloni

ngreference

ABO

1

ABO

9q342

ABO

NM_

020469

a3GalNAcT,a3GalT

II

n.a.

354

4

Yama

motoetal(1990b))

MNS

2

MNS

4q282-q311

GYPA

NM_

002099

Glyco

phorinA

I

36

131

CD235a

43

SiebertandFukuda(1986)

GYPB

NM_

002100

Glyco

phorinB

I

24

72

CD235b

SiebertandFukuda(1987)

P

3

P1

22q112-ter

P1

a4GalT?

-

n.a.

1

Rh

4

RH

1p3613-p343

RHD

RHCE

NM_

016225

NM_

138618

RhD

RhCE

M-12

M-12

3032

417

417

CD240D

CD240CE

48

Aventetal(1990),

Cheri

f-Zaharetal(1990),

LeVa

nKimetal(1992),

Arceetal(1993),

Kajii

etal(1993)

Lutheran

5

LU

19q132

LU

NM_

005581

Luthe

ranglycoprotein(IgSF)

I

7885

597

CD239

19

Parso

nsetal(1995)

B-CA

M

(IgSF)

I

557

Kell

6

KEL

7q33

KEL

NM_

000420

Kellg

lycoprotein

II

93

732

CD258

24

Leeetal(1991)

Lewis

7

LE

19p133

FUT3

NM_

000149

a3/4F

ucT

II

n.a.

361

6

Kukowska-Latalloetal(1990)

Duffy

8

FY

1q21-q25

DARC

NM_

002036

DARC,

Duffyglycoprotein

M-7

3545

338

CD234

6

Chaudhurietal(1993)

Kidd

9

JK

18q11-q12

SLC14A1

NM_

015865

HUT,

Kiddglycoprotein

M-10

50

389

3

Olivesetal(1994)

Diego

10

DI

17q12-q21

SLC4A1

NM_

000342

AE-1,

Band3

M-14

90

911

CD233

21

Tanneretal(1988),

Luxe

tal(1989)

Yt

11

YT

7q22

ACHE

NM_

015831

Acety

lcholinesterase

GPI

160

557

2

Lietal(1991)

Xg

12

XG

Xp

2232

XG

NM_

175569

Xgglycoprotein

I

2229

180

CD99

2

Darlingetal(1986),

Ellisetal(1994)

Scianna

13

SC

1p34

ERMAP

NM_

018538

ERMAP(IgSF)

I

60

475

4

Yeet

al(2000)

Dombrock

14

DO

12p132-p121

ART4

NM_

021071

ADP-

ribosyltransferase4

GPI

5457

314

5

Gubinetal(2000)

Dombrockglycoprotein

Colton

15

CO

7p14

AQP1

NM_

000385

CHIP

,Aquaporin-1

M-6

28or50

269

3

PrestonandAgre(1991)

Landsteiner-

Wiener

16

LW

19p132-cen

ICAM4

NM_

022377

ICAM

-4

LWg

lycoprotein(IgSF)

I

42

241

CD242

3

Bailly

etal(1994)

Chido-

Rodgers

17

CH/RG

6p213

C4A

C4B

NM_

007293

NM_

000592

Complementfactor4A

Complementfactor4B

S S

n.a.

1741

1744

9

Yuet

al(1986),

Yu(1991)

Hh

18

H

19q133

FUT1

NM_

000148

a2FucT

II

n.a.

365

CD173

1

Kelly

etal(1994)

Kx

19

XK

Xp

211

XK

NM_

021083

Xkglycoprotein

M-10

37

444

1

Hoetal(1994)

Gerbich

20

GE

2q14-q21

GYPC

NM_

002101

GPC

I

32

128

CD236R

7

Colin

etal(1986)

GPD

I

23

107

CD236

Cromer

21

CROM

1q32

DAF

NM_

000574

DAF

GPI

70

347

CD55

12

Caras

etal(1987),

Medo

fetal(1987)

Knops

22

KN

1q32

CR1

NM_

000573

CR1

I

170280

1998

CD35

8

Wongetal(1989)

Indian

23

IN

11p13

CD44

NM_

000610

Herm

esantigen

I

80

341

CD44

2

GoldsteinandButcher(1990),

Harn

etal(1991)

Review

760 2004 Blackwell Publishing Ltd, British Journal of Haematology, 126, 759771


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Table

1.

(continued)

ISBT

Name

ISBT

number

ISBT

system

symbol

Ch

romosome

loc

ation

ISGN

gene

symbol

Genbank

account

number*

Geneproduct

Protein

type

Apparent

mass

(kDa

)

Number

ofamino

acids

CD

number

Numberof

antigens

Cloningreference

Ok

24

OK

19p133

BSG

NM_

001728

Neurothelin,

basigin

I

356

9

248

CD147

1

Guoetal(1998)

Raph

25

RAPH

11p155

MER2

NM_

004357

MER2

M-4

40

253

CD151

1

Hasegawaetal(1996)

JMH

26

JMH

15q223-q23

SEMA7A

NM_

003612

H-Sema-L

GPI

758

0

656

CD108

1

Yamadaetal(1999)

I

27

I

6p24

GCNT2

NM_

145649

b6GlcNAcT

II

n.a.

400

1

Bierhuizenetal(1993)

Globoside

28

GLOB

3q25

B3GALT3**

NM_

033169

b3GalNAcT1,Psynthase

II

n.a.

331

1

Amadoetal(1998)

GIL

29

GIL

9p13

AQP3

NM_

004925

Aquaporin-3

M-6

45

292

1

Inaseetal(1995)

*SeveraldifferentGenBankentriesmay

existforeachsystem;n.a.,notapplicable.Mostaccessionnumbersgivenwereretrievedfrom

http://www.gene.ucl.ac.uk/cgi-bin/nomenclature/searchgenes.p

linJuly

2003.

TypeIandIIaresinglemembranepa

ssmoleculeswiththeiramino-orcarboxyterm

inalsoutsidethecell(insidetheGolgiforgly

cosyltransferases)respectively.

M-nisamultimembranepassmolecule

thattraversesthemembranentimes;G

PIisamoleculeanchoredtotheRBCmemb

raneviaaglycosylphosphatidylinositollink;S

isamoleculethatisfoundinitssolubleform

inplasmabuthasbeen

adsorbedtotheRBCmembraneandc

ovalentlyboundtolysineresidues.

Insomeinstancesthenumberofaminoacidsgivenmayvarybetweendifferentva

riants/formsofthemolecule.

Whilsttheprimarygeneproductistheglycosyltransferasegiven,thebloodgroup

antigensarecarriedbycarbohydratestructuresonglycoproteinsand/orglycolipids.

ThesizegivencorrespondstothefulllengthofC4.ObservethattheC4dfragmen

tonlyisadsorbedandboundtotheRBCandcarriestheCH/RGantigens.

**Currentgenenamebasedontheerr

oneousassignmentofthegeneproductasab3-galactosyltransferase.

Review

2004 Blackwell Publishing Ltd, British Journal of Haematology, 126, 759771 761


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ment of these antigens to a specific blood group system.

However, there are exceptions in both cases. For example, the

gene responsible for expression of P1 antigen in the P blood

group system has not been identified. Despite this, it has been

acknowledged as a system of its own since it was declared

independent of all other blood group systems. The opposite is

true for the Pk blood group antigen, currently residing in

collection 209. The locus responsible for Pk blood group

antigen expression was unambiguously shown to be a 4-a-

galactosyltransferase gene (A4GALT) on the long arm of

chromosome 22 (Steffensen et al, 2000). However, since its

relation to the P blood group system (also coded for by a locus

on the long arm of chromosome 22 according to family

studies) is unclear, it remains in the GLOB collection until this

issue has been resolved.

Molecular mechanisms that generate bloodgroup diversity

Diversity in the human genome arises through a number of

different mechanisms (Table III) but the most common is the

SNP. SNPs are predicted to account for much of the diversity

observed between subjects of the same or even closely related

species. The 142 million SNPs originally reported in a genomic

map of human genetic variation was just a first hint of the true

number of SNPs (Sachidanandamet al, 2001). Since the initial

sequencing and mapping of the human genome, the number of

SNPs reported has grown exponentially and over 2 million

SNPs have been identified and validated (http://www.ncbi.-

nih.gov/SNP/index.html).

SNPs in exon sequences

The SNPs can be silent or affect the translated gene product,

either as missense mutations, or non-sense mutations. Single

amino acid substitutions resulting from missense mutations in

exon sequences are common. Accordingly, it is not surprising

that it has been estimated that two thirds of all blood group

antigens are defined by missense SNPs in blood group genes

(Reid & Yazdanbakhsh, 1998). SNPs associated with some

important pairs of antithetical antigens are listed in Table II.

Non-sense SNPs are those that cause an immediate (and

premature) stop codon e.g., a T>A mutation in the FY gene

occurring at different points in three unrelated people of the

Fy(ab) phenotype resulted in the substitution of tryptophan

by a premature stop codon (Rios et al, 2000a). The mutationsat nucleotide 287, 407 or 408 demonstrate the effect of

premature stop codons on protein synthesis, since there was no

detectable Duffy protein present on the RBCs.

SNPs cannot only alter the antigen expressed by a certain

blood group molecule but also modify the number of copies

expressed in the RBC membrane. This is well illustrated by the

many RHD alleles in which a SNP results in weakened

expression of the D antigen. Indeed, a single nucleotide change

can have a profound effect on the amount of D antigen

expressed at the RBC surface, reducing the amount by as much

Table II. Single nucleotide polymorphisms (SNPs) associated with selected antigens in some important blood group systems.

System symbol Antige n 1 Critical SNP (amino acid change) Antigen 2 Reference

ABO A C796A, G803C* (Leu266Met, Gly168Ala) B Yamamoto et al(1990a)

MNS M C59T, G71A, T72G (Ser1Leu, Gly5Glu) N Siebert and Fukuda (1986)

S T143C (Met29Thr) s Siebert and Fukuda (1987)

RH C T307C* (Ser103Pro) c Mouro et al (1993), Simseket al(1994)

E C676G (Pro226Ala) e Mouro et al (1993), Simseket al(1994)

LU Lua A252G (His77Arg) Lub El Nemer et al (1997), Parsons et al(1997)

Aua A1637G (Thr539Ala) Aub Parsons et al(1997)

KEL K1 T698C (Met193Thr) K2 Lee et al(1995)

Kpa T961C (Trp281Arg) Kpb Lee et al(1996)

FY Fy a G125A (Gly42Asp) Fy b Chaudhuri et al (1995), Iwamoto et al(1995),

Mallinson et al (1995), Tournamille et al(1995b)

JK Jk a G838A Asp280Asn Jk b Olives et al(1997)

DI Dia C2561T (Leu854Pro) Dib Bruce et al(1994)

Wra G1972A Glu658Lys Wrb Bruce et al(1995)

YT Yta C1057A (His353Asn) Ytb Bartels et al(1993)

SC Sc1 G169A (Gly57Arg) Sc2 Wagner et al(2003)

DO Doa A793G (Asn265Asp) Dob Gubin et al(2000)

CO Co

a

C134T (Ala45Val) Co

b

Smith et al(1994)LW LWa A308G (Gln70Arg) LWb Hermand et al(1995)

CROM Tca G155T (Arg18Leu) Tcb Lublin et al(2000)

IN Ina C252G (Pro46Arg) Inb Telen et al(1996)

*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.

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as 100-fold (Wagner et al, 1999, 2000). Another interesting

example is the Fyx phenotype, in which a missense mutation

that encodes an amino acid change in an intracellular loop of

the molecule results in less Duffy glycoprotein on the cell

surface (Olsson et al, 1998; Parasol et al, 1998; Tournamille

et al, 1998). The SNP that encodes the Kpa polymorphism not

only results in the altered antigen specificity but also affects

trafficking of the Kell glycoprotein to the RBC surface so that

there is a reduced expression of Kell in the cell membrane

whilst increased amounts can be found intracellularly (Ya-

zdanbakhshet al, 1999).

Evolutionary pressure from various pathogens is generally

thought to be responsible for the generation of genetic

variants, the host effects of which determine whether or not

they will survive over time. This has been discussed with a

main focus on microbial pathogens, e.g. relating to the

differences in carbohydrates expressed on cell surfaces

(Gagneux & Varki, 1999) but there is also strong evidence

for the role of malaria on the genetic variants of some of the

integral RBC membrane proteins, such as the Duffy glycopro-

tein and the RBC anion exchanger (AE1; band 3) (Milleret al,1976; Bruce & Tanner, 1999).

SNPs in introns and regulatory regions

The splice sites are crucial for exon fusion when the introns are

removed by the splicing machinery of the cell during the

maturation of hnRNA to mRNA. Mutations that affect the

invariant GT at +1 and +2 of the 5-donor splice site or

the invariant AG at 1 and 2 of the 3-receptor splice site

will cause skipping of the preceding or succeeding exons

respectively. Mutations of the less conserved nucleotides of the

splice site recognition sequence can also affect exon processing

and cause exon skipping. The Jknull phenotype in Polynesians

(Irshaidet al, 2000) and some K0phenotypes (Lee et al, 2001)

are examples of how this phenomenon can alter the RBC

phenotype. Individuals whose RBCs carry null phenotypes,

such as the Jknull and K0 phenotypes, are at risk of immun-

ization by blood transfusion or pregnancy and once immun-

ized, will require the provision of rare blood for any further

transfusion therapy. The SsU+w phenotype in African-

Americans also arises from exon-skipping events due either to

a mutation in the intron 5 splice site or to mutations in exon 5

that activate a cryptic splice site (Storryet al, 2003). The SNP

responsible for the Dr(a) phenotype in the Cromer blood

group system, also creates a cryptic splice site in the DAFgene

that is used preferentially (Lublin et al, 1991). The product of

the alternative splicing is not found on the RBC surface and

consequently, Dr(a) RBCs express only 40% of normal levels

of DAF.

The SNPs that occur in the regulatory elements, such as the

promoter or enhancer regions of blood group genes, canmodify or abolish antigen expression. A well-known example

of such modification is the altered tissue distribution of the

Duffy blood group antigens commonly found in individuals of

African origin. A disruption of the GATA-1 motif in the

promoter region of the FY*B gene by a single nucleotide

substitution abolishes erythroid expression whilst the molecule

is expressed normally in other tissues (Tournamille et al,

1995a). This mutation is a perfect illustration of evolutionary

pressure exerted by a pathogen since the Duffy protein is the

exclusive receptor on mature RBCs for the malarial parasite,

Table III. Molecular mechanisms that generate diversity in blood group genes.

Type of change Molecular mechanism Example of gene event Phenotypic consequence

Antithetical antigen Missense SNP KEL 698C>T K2fiK1 antigen

Novel antigen Missense SNP GYPB161G>A Mit+

Equal crossover between homologous genes GYP(B-A) Ss+wU, Dantu+

DNA conversion between homologous genes RH(D-CE-D) DVI, BARC+

Exon duplication GYPC.Lsa Ls(a+)

Reduced amount of

expected antigen

Missense SNP ABO646T>A Ax

FY298C>T Fy x

CROM596C>T Dr(a)

Splice site mutation GYPB intron 5 +5g>t SsU+w

XK intron 2 +5g>a McLeod phenotype:

weakened Kell antigens

No protein product Non-se nse SNP DO 442T>C Gy(a)

Nucleotide deletion RHAG 1086delA RhnullCO 232delG Co(ab)

Mutation in transcription motif FY46T>C Fy(ab)

Splice site mutation DO intron 1 2a>g Gy(a)

Gene deletion DRHD D

D

GYPA En(a)Modifying gene In(LU) Lu(ab)

*SNP, single nucleotide polymorphism; D, deletion.

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Plasmodium vivax (Miller et al, 1976). The Duffy protein is

absent from the RBCs of up to 100% of native West Africans

and consequently, these individuals are protected fromP. vivax

infection. Furthermore, the same evolutionary pressure is

proposed to have driven the identical mutation in the GATA-1

sequences of the FY*A allele in a Papua New Guinean

population but, interestingly, the mutation is thought to be a

much more recent and unlinked event (Zimmerman et al,

1999).

Other mechanisms that contribute to blood group diversity

While single nucleotide changes can have far-reaching conse-

quences on gene product expression and function, there are

also other mechanisms that contribute to diversity. Gene

rearrangements due to recombination or gene conversions

between homologous genes, such as those encoding the Rh and

MNS blood group systems, can affect blood group expression

in many different ways (Blumenfeld & Huang, 1997; Avent,

2001). Surprisingly, the same is true for ABO where only a

single gene locus results in multiple hybrid alleles, giving rise to

unexpected phenotypes (Fig 1) (Olsson & Chester, 2001).

Recombination between the two homologous genes in the Rhand MNS blood group systems is common and can lead to

many different kinds of phenotype. Examples of exchange

between homologous genes in trans are common in the MNS

system where hybrids of GPA and GPB are created by unequal

crossover or gene conversion events (Fig 2A) (Blumenfeld &

Huang, 1997). New antigens arise as a result of the novel

amino acid sequences generated by the hybrid genes. The

hybrid molecules that carry unusual phenotypes in the Rh

blood group system are thought to be generated by crossover

between the RHD and RHCE genes in cis (Fig 2B) (Wagner

et al, 2001), that may alter or abolish the expression of

expected antigens and create novel antigens/phenotypes. For

example, the partial D phenotype, DVI type I, results from a

RH(D-CE-D) hybrid in which exons 4 and 5 of RHD are

replaced by the corresponding exons of an RHcEallele (Avent

et al, 1997; Huang, 1997). The hybrid protein expresses a

qualitatively and quantitatively altered D antigen. A similar

exchange of RHD with exons 4, 5 and 6 of an RHCe allele

produces a hybrid protein with a qualitatively identical D

antigen, as determined by monoclonal antibody studies;

however, more copies of the D antigen are present and these

RBCs also express the low incidence antigen, BARC (Mouro

et al, 1994; Tippett et al, 1996).

Non-sense mutations, such as nucleotide deletions or

insertions, often abolish or decrease blood group expression

by causing a shift in the open reading frame of the sequence

such that the amino acids encoded after the mutation are

completely different. For example, in the ABO system, two

different single nucleotide deletions in the consensus A1

sequence have been shown to account for the common O and

A2 blood groups. These are illustrated in Fig 3 (Yamamoto

et al, 1990a, 1992).

Not surprisingly, the deletion of whole genes or parts ofgenes can result in loss of blood group antigen expression as

exemplified by the following reports concerning the MNS

(Huanget al, 1987; Rahuelet al, 1988), RH (Wagner & Flegel,

2000), JK (Irshaid et al, 2002), H (Koda et al, 1997) and GE

(Colinet al, 1989) blood group systems.

Duplication of genetic material can result in the formation of

a novel antigen, for example, the nucleotide sequence created

by the exon 3-exon 3 duplication in the GYPC.Lsa variant gene

encodes the Lsa antigen (Reid et al, 1994). Conversely, a

duplication event may result in the loss of an existing antigen.

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 aBallele to generate aBO1v 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 Ballele 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.

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The best example of this is the 37 bp nucleotide duplication

that occurs at the intron 3/exon 4 border in the RHD

pseudogene (Singleton et al, 2000). The duplication results in

an alteration of the reading frame and an eventual premature

stop codon so that no RhD protein is found on the RBCs.

In theABOgene, a 43 bp minisatellite motif 4 kbp upstreamfrom exon 1, with the ability to bind the transcription factor

CBF/NF-Y has been suggested to govern transcription in an

enhancer-like way (Kominato et al, 1997). Allele-related vari-

ation in the number of repeats was observed in samples of

different ABO genotypes: A1 and O2 alleles having one copy

only while A2, B, O1 and O1v alleles had four copies (Irshaid

et al, 1999). In an experimental model, four repeats (associated

with the common A2, B and O1/O1v alleles) produced

approximately 100 times more mRNA than a single repeat

(found in A1 andO2 alleles) (Yu et al, 2000).

Blood group genes that control carbohydrate antigens

All genes encode proteins but not all blood group genes encode

blood-group-carrying proteins. The reason, of course, is that

not all blood groups antigens are of protein nature. This

apparent anomaly was indeed confusing to the pioneers whohad elucidated the biochemical basis of blood groups like

ABO, H and Lewis. On one hand, DNA was supposed to code

for proteins but, on the other hand, these carbohydrate blood

groups were definitely inherited characters. The solution came

when Watkins hypothesized that the genes encoded blood-

group-specific glycosyltransferases (Watkins, 1974). This hypo-

thesis held true, although today researchers still struggle to

clarify the genetic heterogeneity underlying variant carbohy-

drate blood groups. In theory, any mutation that changes the

enzymatic properties of the primary gene product including

Fig 2. Mechanisms that generate hybrid genes

in the MNS and Rh blood group systems. (A)

DNA exchange between the GYPA and GYPB

genes intrans, either by unequal crossover or by

gene conversion, creates novel sequences that

are recognized as blood group antigens. (B)Crossover of the RHgenes in cis creates hybrid

genes that have altered expression of expected

antigens and may create novel antigens. SMPis

an unrelated gene. Genes are illustrated in a

53 direction unless noted otherwise. Novel

sequences are indicated by the parenthesis.

Review



8/13

activity, substrate and acceptor preference may cause, e.g. a

weak A or B subgroup (Chester & Olsson, 2001). The null

phenotypes O, p, or Bombay result from the inheritance of two

inactive alleles of the respective glycosyltransferase gene. In all

three genes, inactivating mutations have been found through-

out the coding sequence. For ABO, however, a single-

nucleotide deletion is the predominant cause of the blood

group O phenotype whilst other causes are infrequent or rare.

Currently, the number of alleles at the ABO locus approaches a

hundred and reaches a degree of complexity due to point

mutations and hybrid allele formation that is only matched by

theRHand MNS loci.

Heterogeneity of null phenotypes

By comparison with theABO locus, most of the protein-based

systems are relatively simple and a polymorphism defined at

the genetic level can almost always be correlated with the

expression of a certain blood group antigen. However, in

genomic DNA-based analysis, the interpretation of results can

be confounded by the existence of null phenotypes. Clearly,

any mutation in the gene that results in the failure of the

antigen-carrying molecule to be expressed at the RBC surface

will, in fact, be a null mutation. Because some of these

mutations occur relatively commonly, it is important toinclude their detection together with assays for common

phenotype prediction in order to avoid false positive results.

For example, it is necessary to test for the GATA-1 mutation in

the FY gene described above, when determining Fya and Fyb

antigen status but not for the other very rare mutations that

result in the Fy(ab) phenotype. Similarly, in the Nordic

population, it should be considered to include detection of

the 871T>C mutation in the JKgene that is the basis for the

Jk(ab) phenotype in the Finnish people (Irshaid et al, 2000).

The heterogeneity of the molecular bases of these phenotypes is

a major problem for all DNA-based prediction of blood

groups.

Most null blood group phenotypes are the result of

molecular changes in the gene that encodes the carrier

molecule. However, there are important interactions between

proteins at the cell surface and with the cytoskeleton and

therefore mutations that change the expression of an interact-

ive protein can affect the proteins around it. Mutations in

RHAG that stop the expression of the Rh-associated glyco-

protein (RhAG) also prevent the expression of the RhD and

RhCE proteins the so-called regulator type of Rhnullphenotype (reviewed in Daniels, 2002). Similarly, mutations

leading to the absence of the XK protein in the red cell

membrane results in the weakened expression of Kell blood

group antigens (Daneket al, 2001; Russo et al, 2002).

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 onfunctional 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;

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.

Review



9/13

van der Schoot et al, 2003). Although there are some current

limitations to the technique, the advantages of this non-

invasive 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 detec-

tion, 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 therelationship 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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