JOURNAL OF COAGULATION DISORDERS REVIEW ARTICLE

Bernard Soulier Syndrome: A Rare Bleeding Disorder with

a Wide Range of Genetic Defects
Basma Hadjkacem1, Ikram Ben Amor2, Mariem Smaoui2, Lobna Maalej2, Jalel Gargouri2 and Ali Gargouri1
Affiliations: 1Laboratoire de Génétique Moléculaire des Eucaryotes, Centre de Biotechnologie de Sfax, BP‘‘K’’3038, Sfax, Tunisia and 2Centre Régional de Transfusion
Sanguine de Sfax, Safx, Tunisia

A B S T R A C T

Bernard Soulier Syndrome (BSS) is a rare inherited bleeding disorder caused by a quantitative or qualitative defect in glycoprotein (GP)Ib-
IX-V complex, the receptor for the von Willebrand factor (vWF). This complex plays a major role in platelet adhesion at sites of vascular injury
through binding to vWF. It is also involved in the thrombin induced platelet activation. BSS is usually inherited in an autosomal recessive
manner and is characterized by a prolonged bleeding time, thrombocytopenia, and giant platelets. Clinical manifestations include a series of
purpura, epistaxis, menorrhagia, gingival, and gastric bleeding. Diagnosis is based on prolonged skin bleeding time, macrothrombocyto-
penia, defective ristocetin-induced platelet aggregation, and the exploration of GPIb-IX-V complex expression. The complex is composed of
four subunits: GPIba, GPIbb, GPIX, and GPV, but the principal candidate genes for this disease are GPIba, GPIbb, and GPIX. These genes are
unique in the genome and share the scarcity of introns with one or two introns per gene. In this review, we give an overview of the mutations
occurring in the candidate genes with an emphasis on compound heterozygous mutations as well as on founder mutations.

Keywords: Bernard Soulier syndrome, bleeding disorder, GPIb-IX-V complex, thrombocytopenia, giant platelets, founder mutation,
compound heterozygous

Correspondence: Ali Gargouri, Laboratoire de Génétique Moléculaire des Eucaryotes, Centre de Biotechnologie de Sfax, BP‘‘K’’3038, Sfax,
Tunisia. Tel/Fax:
216 74 440 454; e-mail: faouzi.gargouri@cbs.rnrt.tn

GENERAL INFORMATION ON THE SYNDROME
Bernard Soulier Syndrome (BSS) was described more than
60 years ago as a severe, and potentially fatal, congenital
bleeding disorder. The first case was reported in 1948 by Jean
Bernard and Jean-Pierre Soulier on a young male patient with
a prolonged bleeding time, low platelet counts, and extremely
large platelets. They termed the disorder ‘‘congenital hemor-
rhagiparous thrombocytic dystrophy’’ [1]. Since then, some
individuals have been described with a similar disorder. Based
on data reported concerning European, North American, and
Japanese populations, the frequency of homozygous BSS has
been estimated to be approximately one in one million [2]
and, according to the Hardy-Weinberg Law, the frequency of
heterozygotes is 1 in 500 [3].
The BSS is a rare inherited disorder usually transmitted in
an autosomal recessive manner and occurring in persons
whose parents are close relatives. An autosomal dominant
with heterozygous state also has been found but rarely
reported. This form was characterized by mild or no clinical
symptoms and normal in vitro platelet function [3, 4].
Thrombocytopenia results in decreased survival platelets
and inefficacy platelets production [5]. BSS patients may
repeatedly require transfusion of platelets.
BSS is characterized by defective platelet adhesion to
vascular injury as a consequence to quantitative or qualitative
defects on GPIb-IX-V complex (composed by GPIba, GPIbb,
GPIX, and GPV glycoproteins), which is the principal receptor
for the von Willebrand factor (vWF) [6, 7]. We shall recall
here that this complex is involved in adhesion of platelets to
vascular injury whereas the GPIIb-IIIa is involved in platelets
aggregation by fixing the fibrinogen [8].
Different diagnostic parameters have been used to classify
inherited thrombocytopenia including the degree of bleeding,
inheritance trait, platelet function and kinetics, and clinical
abnormalities. Thanks to the mean platelet volume, we can
distinguish between macrothrombocytopenia and thrombo-
cytopenia. Patients with increased platelet size can be
classified in several forms of inherited macrothrombocyto-
penia such as BSS, May-Hegglin anomaly, gray platelet
syndrome, von Willebrand disease, Montreal platelet syn-
drome, and Epstein, Fechtner, and Sebastian syndromes. All
of them have their specific features but the molecular
mechanisms that cause hereditary giant platelet disorders
are not known in detail except those for BSS [3].
BERNARD SOULIER SYNDROME (BSS)
PATIENTS
Until now, more than 100 BSS cases have been described.
Both male and females are concerned by this disease, the
male/female ratio is 1:1. All of them showed giant platelets in
their blood smear (sometimes larger than 6 mm and being
able to reach 10 mm, while normal platelets are 23 mm),
prolonged skin bleeding time (
15 min) and thrombocyto-
penia (between 1010 to 1011 platelets/l compared to 1.51011

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Journal of Coagulation Disorders
to 41011 platelets/l in healthy persons). Clinical manifesta-
tions appear from childhood and usually include frequent
episodes of epistaxis, purpura, menorrhagia, or gingival
bleeding [2]. Some patients can show gastrointestinal
hemorrhage. Severe bleeding occurred in the case of trauma,
surgical intervention, and in menses. Chronic easy bruising
and frequent hematomas are rarely reported [9]. Pregnancy in
BSS patients may present complications of varying severity
[10].
While the platelets of patients aggregate normally in
response to agonists such as adenosine diphosphate (ADP),
collagen, epinephrine, arachidonic acid, they present reduced
or absent ristocetin-induced platelet aggregation. In addition,
all BSS patients have decreased or absent expression of the
GPIb-IX-V glycoproteins. The diagnosis is based on all those
observations and is confirmed by an aggregation test using an
aggregometer and by flow cytometry using specific antibodies
recognizing one or more proteins of the complex [2, 11, 12].
The GPIIb-IIIa complex, normally expressed on the platelets
surface of healthy persons and BSS patients, serves as a
positive control. Those specialized laboratory tests are
essential to avoid confusion between BSS and other platelet
disorders such as May-Hegglin or idiopathic thrombocyto-
penic purpura [2, 13]. Based only on clinical manifestations,
many patients had been erroneously diagnosed with immune
thrombocytopenia and were treated with steroids without
response [14].
THE CONSTITUENTS OF GPIB-IX-V COMPLEX
The GPIb-IX-V glycoprotein complex of platelet membrane
plays a major role in primary hemostasis: it mediates
adhesion to the vessel wall at sites of injury by binding
vWF, this ligation can transduce signals to the platelet
cytoplasm to initiate a cascade of events that leads to the
formation of the hemostatic platelet plug. Note that in the
absence of a functioning vWF receptor, platelets cannot
adhere to vascular subendothelium under high shear stress.
In addition, the complex facilitates the ability of thrombin at
low concentrations to activate platelets [2, 15]. The complex
is expressed at a high density on the cell surface (24,000
copies/platelet) [16]. It is formed by the association in 2:2:2:1
stoichiometry of four proteins that belong to the leucine-rich
motif (LRM) family of proteins. The GPIb consists of two
disulfide linked subunits, GPIba (145 kD) and GPIbb (22 kD)
while GPIX (20 kD) and GPV (82 kD) bind to GPIb
noncovalently [2].
The largest glycoprotein, GPIba, consists of a N-terminal
globular domain that contains seven tandem leucine-rich
repeats, the integrity of which region is essential to provide a
normal function of the GPIb-IX-V complex [17]. It contains
three sulfated tyrosins Tyr 276, Tyr 278, and Tyr 279 also
[18]. The tyrosine sulfation constitutes a posttranslational
modification indispensable to ensure interaction with the
vWF [19]. This globular domain contains both the vWF
binding site and thrombin binding site. The GPIba protein
also contains a highly O-glycosylated macroglycopeptide
mucin core that resembles a stem connecting the N-terminal
JCD 2010; 000:(000). Month 2010
domain to a platelet plasma membrane, a single transmem-
brane sequence, and a cytoplasmic tail [2, 20].
The GPIbb protein has a N-terminal extra cellular domain
that contains a cysteine knot region, which is essential for
interaction with GPIX [21]. This protein also includes a
transmembrane domain with a single leucine-rich repeat
motif and a short cytoplasmic tail, phosphorylated at Ser166
by the PKA (Protein Kinase AMPc dependant). This kinase
negatively regulates vWF fixation on the GPIb-IX-V complex
[22].
The GPIX has only one leucine-rich repeat motif, a
transmembrane domain and a short cytoplasmic tail. This
glycoprotein is essential for the correct assembly of the GPIb-
IX-V complex on a platelet membrane [23].
The GPV contains an extra cellular domain with 15 leucine-
rich repeats and 8 glycosylation sites [24], a cleavage site by
thrombin in the amino terminal transmembrane domain and
a short intracellular tail [25]. GPV is essential to bind
thrombin with high affinity [23].
The GPIb-IX-V complex is formed within minutes in the
endoplasmic reticulum before being transported into the
Golgi cisternae: the four polypeptides are synthesized and
transported in the endoplasmic reticulum where they are
assembled. The complex is then transported into the Golgi
cisternae to be modified [23].
The studies based on in vitro cells transfection showed that
the assembly of glycoproteins to form the GPIb-IX-V complex
is done in the reticulum before reaching the plasma
membrane [26]. Approximately 160 min are required for the
complex to be fully processed and to appear on the plasma
membrane.
About 25% of GPIba expressed on incomplete GPIb-IX or
GPIb-IX-V complexes are degraded through a nonlysosomal
pathway. Over 60% of GPIba are degraded by lysosomes
when expressed only with GPIbb or GPIX. This finding
indicates that the presence of both GPIbb and GPIX is
required for efficient processing and targeting of GPIba to
the plasma membrane. The absence of either GPIbb or GPIX
increased the rate of GPIba degradation [23].
GLYCOPROTEIN GENES INVOLVED IN
BERNARD SOULIER SYNDROME (BSS)
Each glycoprotein of the complex is encoded by a single
copy gene located on different chromosomes: GPIba gene is
located on 17p12, GPIbb on 22q11.2, GPIX on 3q21, and GPV
on 3q29 [2730]. Molecular characterization of the four
genes involved in the complex shows common structural
features despite their different chromosomal locations. All
four genes are relatively devoid of introns and, with the
exception of GPIbb, contain their entire coding region within
one exon. GPIbb gene contains two exons (36 bp and 918 bp)
separated by one intron (274 bp), the open reading frame
(ORF) begins in the first exon and finishes in the second one
[31]. The GPIX gene is composed by three exons (72, 126, and
2 www.slm-hematology.com

675 pb, respectively) and two introns with the ORF contained
in the third exon [24].
Molecular investigations of numerous BSS patients showed
that only three genes are responsible of the disease: GPIba,
GPIbb, and GPIX. No mutations have been reported within
the GPV gene [32].
Bernard Soulier patients and the transfection of hetero-
logous cells have indicated that GPIba, GPIbb, and GPIX
proteins are necessary for efficient expression of the complex
whereas GPV is not essential [2, 33]. The modification of a
single constituent will affect expression of the entire com-
plex. This has important implications in pathology. For
example, when GPIbb is defective (Trp21Stop, Ser23Stop,
and Ala80), the GPIX and GPIba glycoproteins are synthe-
sized but they are unable to form a complex [9, 32, 34]. This
confirms the role of GPIbb in the correct assembly and
stability of the GPIb-IX complex on the platelet surface.
Several BSS mutations lead to deficient GPIba expression on
the platelets surface of patients.
BERNARD SOULIER SYNDROME (BSS)
MUTATIONS
Until 2006, 47 different genetic defects associated with BSS
have been identified: 20 mutations in GPIba, 16 mutations in
GPIbb, and 11 in GPIX [13]. Recently, several novel mutations
have been described (see Table 1).
Five mutations in GPIba, with
. Three frameshift: C3221 insertion [35]; TGAG dele-
tion starting from the last base of the codon for Ser23
[36] and TTCACATG deletion at positions 1136_1143
[37].
. Homozygous missense mutation: Trp207Gly [38].
. Heterozygous missense mutation: Asn41His [54].
Two mutations in GPIbb:
. A nonsense mutation Ser23Stop [34].
. Compound heterozygous for Ser23Stop, Asp51Gly,
and Ala55Pro [39].
This raises the number of reported mutations to 54
(Table 1). We note that there is no hot spot mutation.
Molecular defects can be classified as follows:
. Missense mutations or short in-frame deletions that
give rise to normal or a slightly modified protein
leading to a dysfunctional receptor or to an abnormal
complex with decreased surface expression.
. Nonsense mutations giving rise to shorter proteins.
. Insertions or deletions leading to a frame shift, a novel
polypeptide sequence or a premature Stop [40].
. Compound heterozygosity has also been reported in
BSS patients.
In GPIba, two compound heterozygote BSS patients have
been described with a maternal allele with a T insertion at
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Bernard Soulier syndrome with wide range of genetic defects
position 1418 causing a translational frameshift and prema-
ture polypeptide termination, and a paternal allele with a
T715A substitution changing Cys209 to Ser [41]. Another
compound heterozygous has also been described having the
same T insertion at position 1418 and a second mutation
consisting in a deletion of a single base (A) within the
7-adenine repeat at cDNA position 1438 to 1444 [42].
The BSS patient with two homozygous mutations in GPIba
has also been described. The patient has one allele containing
a novel four base-pair deletion (TGAG) that eliminated the
last base of the codon for Ser39 (AGT) and the entire codon
for Glu40 (GAG), causing a frame shift that yielded a stretch
of 51 amino acids before a premature stop codon. The second
allele also contained a frame-shift mutation, caused by the
deletion of the last two bases of the codon TAT for Tyr492.
This second allele has been identified as the cause of the
Bernard Soulier syndrome in patients of northern European
ancestry based on patients’ haplotype of polymorphic mar-
kers [43].
In a GPIbb gene, the first compound heterozygote reported
described a Japanese case presenting two mutations at
residues 88 and 108 of the GPIbb protein. This patient
presented a variant of the BSS phenotype in which neither
thrombocytopenia nor a bleeding tendency was observed
[44]. The second interesting example concerned another
Japanese boy presenting two independent heterozygous
mutations in the GPIbb gene: Cys122Ser and 1096delG
[45]. The third case is identified in a Tunisian patient having
Ser23Stop mutation in GPIbb gene in a heterozygous state
and two other missense heterozygote mutations in the same
gene: (Asp 51 Gly) and (Ala 55 Pro). The last case is the only
report of BSS showing compound heterozygosity for three
mutations in the same gene [39].
The compound heterozygosity is also observed in a patient
having (Asp 21 Gly) mutation in GPIX [46] and some patients
with the (Asn 45 Ser) in the same gene [14, 47]. A BSS patient
with a single heterozygous missense mutation at GPIba gene
has been described. The mutation converts Tyr to Asp at
residue 54 in the second leucine-rich repeat. This patient was
initially diagnosed with idiopathic thrombocytopenic purpura
[48]. BSS rarely has been reported with deletion in the
DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2,
so the GPIbb mutation is found on only one allele while the
other is deleted [49]. Genetic changes described in the BSS
patients may directly affect the vWF binding site on GPIba,
inhibit the association of GPIb and GPIX following protein
synthesis, or affect posttranslational modifications that may
influence the function of the complex [2, 23]. No significant
relationship was found between the type of mutation, the
defective gene responsible of the phenotype, and the clinical
observations of patients. All of them suffered from hemor-
rhagic symptoms.
FOUNDER MUTATIONS
Some BSS mutations have been described in several families
from different nationalities or in one given population. In
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Journal of Coagulation Disorders

Table 1. Update of BSS Mutations Described in the Three Genes GPIba, GPIBb, and GPIX
Missense mutations or Nonsense
Gene short deletions mutations Frameshift]Stop Other References
GPIba Tyr54]Asp (het) Lanza [13]
(macrothrombocytopenia)
Leu57]Phe Lanza [13]
Cys65]Arg Lanza [13]
Leu123]Pro Lanza [13]
Leu126]Phe Lanza [13]
Leu129]Pro Lanza [13]
Ala156]Val Lanza [13]
^Leu179 Lanza [13]
^169-180/Glu81]Lys Lanza [13]
Cys 209]Ser Lanza [13]
Asn41His (het) Vettore et al [54]
Trp207Gly Rosenberg et al
[38]
^ TGAG starting from the Vettore et al [36]
last base of the codon Ser23


^ 1136 1143 Imai et al [37]
Trp343] Lanza [13]
Stop
Ser444] Lanza [13]
Stop
Trp498] Lanza [13]
Stop
Lys19]Arg
2AA]Stop Lanza [13]
^Ser39Glu40
51AA]Stop Lanza [13]
Arg76]Leu
19AA]Stop Lanza [13]
Val295]Gly
39AA]Stop Lanza [13]
Ser444]Ile
11AA-Stop (het) Lanza [13]
Thr452]Pro
58AA]Stop Lanza [13]
Tyr492]Cys
80AAStop Lanza [13]
C3221 insertion Afrasiabi et al [35]
GPIbb Cys5]Tyr Lanza [13]
Arg17]Cys(Giant platelets) Lanza [13]
Pro29]Leu (het) Lanza [13]
Asn64]Thr Lanza [13]
Pro74]Arg Lanza [13]
Tyr88]Cys Lanza [13]
Tyr88]Cys
Ala108-Pro (het) Lanza [13]
(Giant platelets)
Pro96]Ser
Di George-VCF Lanza [13]
Cys122]Ser (het) Lanza [13]
Trp21]Stop Lanza [13]
Cys116] Lanza [13]
Stop
Trp123] Lanza [13]
Stop

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 Bernard Soulier syndrome with wide range of genetic defects

Table 1 (Continued)

Missense mutations or Nonsense

Gene short deletions mutations Frameshift]Stop Other References

Ser23Stop Hadjkacem et al
[34]
Gly81 ]Ala
86AA]Stop
Di George- Lanza [13]
VCF
^13bp Signal sequence
22AA]Stop Lanza [13]
Ala131]Gly
153AA]Stop Lanza [13]
Promoter Mutation GATA
Di Lanza [13]
George-VCF
Ser23Stop Asp51Gly and Ala55Pro Hadjkacem et al
(het) [39]
GPIX Leu(10)]Pro Lanza [13]
Cys8]Arg Lanza [13]
Asp21]Gly (het) Lanza [13]
Leu40]Pro Lanza [13]
Asn45]Ser (homo and het) Lanza [13]
Phe55]Ser Lanza [13]
Cys73]Tyr Lanza [13]
Asn86]Ala DArg87-Pro89 Lanza [13]
(het)
Cys97]Tyr Lanza [13]
Ala140]Thr Lanza [13]
Trp127] Lanza [13]
Stop

Notes: Regarding the list of Lanza 2006, all new mutations are indicated in bold.
With ^: deletion; amino acids (AA) are in three letter code; (]) change from wild type to mutated AA sequence; Numbering is based on the mature sequence
(GPIX Leu(10) ]Pro is located in the signal peptide); Giant platelets: variant phenotype not a BSS; (het): compound heterozygote; Di George-VCF: Di George
(Velo-Cardio-Facial syndrome) deletion of chromosome region 22q11.2 on the second allele.

GPIba, Leu129Pro was identified in two Afro-American
families [50], two Finnish families [51], and two other
African-American families [11]. Phe55Ser missense mutation
in GPIX was revealed in two families from south Iran [35].
In GPIbb, the Tyr88Cys mutation was found in several
Japanese families [52], a 13-bp deletion of the signal peptide
coding sequence leading to premature termination found in
two related Japanese families [53] and in one patient from
Saudi Arabia [40]. Similarly, the Ala156Val mutation was
identified in several families with the heterozygous BSS
phenotype [3].
Recently, we reported the occurrence of Ser23Stop mutation
in GPIbb in three unrelated Tunisian families and we
suggested that this mutation is founder in the Tunisian
population [39]. To identify the molecular basis of 12
Italian families having a form of autosomal dominant
macrothrombocytopenia, Savoia et al [3] have used a linkage
analysis, mutation screening, and flow cytometry. Linkage
analysis in two large families localized the candidate gene to
chromosome 17p, precisely the GPIba. In six families, they
revealed the presence of a missense mutation (Ala156Val)
with a reduction of the platelets glycoprotein expression as
observed in the heterozygous BSS patients. Authors con-
cluded that patients, initially diagnosed to have autosomal
dominant macrothrombocytopenia, are in reality heterozy-
gous BSS [3].
The Asn45Ser mutation in the GPIX gene has been
described in about 10 unrelated families of different origins:
Finnish, British, Austrian, Swedish, Belgian, and Turkish.
This gene defect is considered the most often identified
molecular defect causing BSS in Caucasians. Koskela et al [51]
suggested that this mutation appears to be an ancient
mutation shared by northern and central European popula-
tions and proposed that Asn45Ser genotyping would be
helpful for a differential diagnosis. Interestingly, thanks to
this mutation, doctors who misdiagnosed three unrelated
German patients with immune thrombocytopenia, corrected
the diagnosis after sequencing the three candidate’s genes for
BSS and they revealed the presence of Asn45Ser mutation in
GPIX [14].
Heterozygous carriers of the bleeding disorder Bernard
Soulier syndrome are occasionally identified as isolated cases
of giant platelet disorder/macrothrombocytopenia or mis-
diagnosed with idiopathic thrombocytopenic purpura (ITP),
which is why the identification of founder mutations is very

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Journal of Coagulation Disorders
important in genetic counseling*to avoid misdiagnosis and
inappropriate therapy.
Disclosure: The author/authors declares/declare no conflict of
interest.
Funding: The authors have received support from the Tunisian
Government to conduct this study.
Acknowledgement: We deeply thank Khmaied Benhaj for reading
the manuscript.
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