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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 for the von Willebrand factor (vWF) [6, 7]. We shall recall
here that this complex is involved in adhesion of platelets to
Bernard Soulier Syndrome (BSS) was described more than
vascular injury whereas the GPIIb-IIIa is involved in platelets
60 years ago as a severe, and potentially fatal, congenital
aggregation by fixing the fibrinogen [8].
bleeding disorder. The first case was reported in 1948 by Jean
Bernard and Jean-Pierre Soulier on a young male patient with Different diagnostic parameters have been used to classify
a prolonged bleeding time, low platelet counts, and extremely inherited thrombocytopenia including the degree of bleeding,
large platelets. They termed the disorder ‘‘congenital hemor- inheritance trait, platelet function and kinetics, and clinical
rhagiparous thrombocytic dystrophy’’ [1]. Since then, some abnormalities. Thanks to the mean platelet volume, we can
individuals have been described with a similar disorder. Based distinguish between macrothrombocytopenia and thrombo-
on data reported concerning European, North American, and cytopenia. Patients with increased platelet size can be
Japanese populations, the frequency of homozygous BSS has classified in several forms of inherited macrothrombocyto-
been estimated to be approximately one in one million [2] penia such as BSS, May-Hegglin anomaly, gray platelet
and, according to the Hardy-Weinberg Law, the frequency of syndrome, von Willebrand disease, Montreal platelet syn-
heterozygotes is 1 in 500 [3]. drome, and Epstein, Fechtner, and Sebastian syndromes. All
of them have their specific features but the molecular
The BSS is a rare inherited disorder usually transmitted in
mechanisms that cause hereditary giant platelet disorders
an autosomal recessive manner and occurring in persons
are not known in detail except those for BSS [3].
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 BERNARD SOULIER SYNDROME (BSS)
symptoms and normal in vitro platelet function [3, 4]. PATIENTS
Thrombocytopenia results in decreased survival platelets Until now, more than 100 BSS cases have been described.
and inefficacy platelets production [5]. BSS patients may Both male and females are concerned by this disease, the
repeatedly require transfusion of platelets. male/female ratio is 1:1. All of them showed giant platelets in
BSS is characterized by defective platelet adhesion to their blood smear (sometimes larger than 6 mm and being
vascular injury as a consequence to quantitative or qualitative able to reach 10 mm, while normal platelets are 23 mm),
defects on GPIb-IX-V complex (composed by GPIba, GPIbb, prolonged skin bleeding time (15 min) and thrombocyto-
GPIX, and GPV glycoproteins), which is the principal receptor 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- domain to a platelet plasma membrane, a single transmem-
tions appear from childhood and usually include frequent brane sequence, and a cytoplasmic tail [2, 20].
episodes of epistaxis, purpura, menorrhagia, or gingival The GPIbb protein has a N-terminal extra cellular domain
bleeding [2]. Some patients can show gastrointestinal
that contains a cysteine knot region, which is essential for
hemorrhage. Severe bleeding occurred in the case of trauma,
interaction with GPIX [21]. This protein also includes a
surgical intervention, and in menses. Chronic easy bruising
transmembrane domain with a single leucine-rich repeat
and frequent hematomas are rarely reported [9]. Pregnancy in
motif and a short cytoplasmic tail, phosphorylated at Ser166
BSS patients may present complications of varying severity
by the PKA (Protein Kinase AMPc dependant). This kinase
[10].
negatively regulates vWF fixation on the GPIb-IX-V complex
While the platelets of patients aggregate normally in [22].
response to agonists such as adenosine diphosphate (ADP),
collagen, epinephrine, arachidonic acid, they present reduced The GPIX has only one leucine-rich repeat motif, a
or absent ristocetin-induced platelet aggregation. In addition, transmembrane domain and a short cytoplasmic tail. This
all BSS patients have decreased or absent expression of the glycoprotein is essential for the correct assembly of the GPIb-
GPIb-IX-V glycoproteins. The diagnosis is based on all those IX-V complex on a platelet membrane [23].
observations and is confirmed by an aggregation test using an The GPV contains an extra cellular domain with 15 leucine-
aggregometer and by flow cytometry using specific antibodies rich repeats and 8 glycosylation sites [24], a cleavage site by
recognizing one or more proteins of the complex [2, 11, 12]. thrombin in the amino terminal transmembrane domain and
The GPIIb-IIIa complex, normally expressed on the platelets a short intracellular tail [25]. GPV is essential to bind
surface of healthy persons and BSS patients, serves as a thrombin with high affinity [23].
positive control. Those specialized laboratory tests are
The GPIb-IX-V complex is formed within minutes in the
essential to avoid confusion between BSS and other platelet
endoplasmic reticulum before being transported into the
disorders such as May-Hegglin or idiopathic thrombocyto-
penic purpura [2, 13]. Based only on clinical manifestations, Golgi cisternae: the four polypeptides are synthesized and
many patients had been erroneously diagnosed with immune transported in the endoplasmic reticulum where they are
thrombocytopenia and were treated with steroids without assembled. The complex is then transported into the Golgi
response [14]. cisternae to be modified [23].
The studies based on in vitro cells transfection showed that
THE CONSTITUENTS OF GPIB-IX-V COMPLEX the assembly of glycoproteins to form the GPIb-IX-V complex
is done in the reticulum before reaching the plasma
The GPIb-IX-V glycoprotein complex of platelet membrane
membrane [26]. Approximately 160 min are required for the
plays a major role in primary hemostasis: it mediates
complex to be fully processed and to appear on the plasma
adhesion to the vessel wall at sites of injury by binding
membrane.
vWF, this ligation can transduce signals to the platelet
cytoplasm to initiate a cascade of events that leads to the About 25% of GPIba expressed on incomplete GPIb-IX or
formation of the hemostatic platelet plug. Note that in the GPIb-IX-V complexes are degraded through a nonlysosomal
absence of a functioning vWF receptor, platelets cannot pathway. Over 60% of GPIba are degraded by lysosomes
adhere to vascular subendothelium under high shear stress. when expressed only with GPIbb or GPIX. This finding
In addition, the complex facilitates the ability of thrombin at indicates that the presence of both GPIbb and GPIX is
low concentrations to activate platelets [2, 15]. The complex required for efficient processing and targeting of GPIba to
is expressed at a high density on the cell surface (24,000 the plasma membrane. The absence of either GPIbb or GPIX
copies/platelet) [16]. It is formed by the association in 2:2:2:1 increased the rate of GPIba degradation [23].
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)
GLYCOPROTEIN GENES INVOLVED IN
while GPIX (20 kD) and GPV (82 kD) bind to GPIb BERNARD SOULIER SYNDROME (BSS)
noncovalently [2]. Each glycoprotein of the complex is encoded by a single
The largest glycoprotein, GPIba, consists of a N-terminal copy gene located on different chromosomes: GPIba gene is
globular domain that contains seven tandem leucine-rich located on 17p12, GPIbb on 22q11.2, GPIX on 3q21, and GPV
repeats, the integrity of which region is essential to provide a on 3q29 [2730]. Molecular characterization of the four
normal function of the GPIb-IX-V complex [17]. It contains genes involved in the complex shows common structural
three sulfated tyrosins Tyr 276, Tyr 278, and Tyr 279 also features despite their different chromosomal locations. All
[18]. The tyrosine sulfation constitutes a posttranslational four genes are relatively devoid of introns and, with the
modification indispensable to ensure interaction with the exception of GPIbb, contain their entire coding region within
vWF [19]. This globular domain contains both the vWF one exon. GPIbb gene contains two exons (36 bp and 918 bp)
binding site and thrombin binding site. The GPIba protein separated by one intron (274 bp), the open reading frame
also contains a highly O-glycosylated macroglycopeptide (ORF) begins in the first exon and finishes in the second one
mucin core that resembles a stem connecting the N-terminal [31]. The GPIX gene is composed by three exons (72, 126, and

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Bernard Soulier syndrome with wide range of genetic defects

675 pb, respectively) and two introns with the ORF contained position 1418 causing a translational frameshift and prema-
in the third exon [24]. ture polypeptide termination, and a paternal allele with a
Molecular investigations of numerous BSS patients showed T715A substitution changing Cys209 to Ser [41]. Another
that only three genes are responsible of the disease: GPIba, compound heterozygous has also been described having the
same T insertion at position 1418 and a second mutation
GPIbb, and GPIX. No mutations have been reported within
consisting in a deletion of a single base (A) within the
the GPV gene [32].
7-adenine repeat at cDNA position 1438 to 1444 [42].
Bernard Soulier patients and the transfection of hetero-
The BSS patient with two homozygous mutations in GPIba
logous cells have indicated that GPIba, GPIbb, and GPIX
has also been described. The patient has one allele containing
proteins are necessary for efficient expression of the complex
a novel four base-pair deletion (TGAG) that eliminated the
whereas GPV is not essential [2, 33]. The modification of a
last base of the codon for Ser39 (AGT) and the entire codon
single constituent will affect expression of the entire com-
for Glu40 (GAG), causing a frame shift that yielded a stretch
plex. This has important implications in pathology. For
of 51 amino acids before a premature stop codon. The second
example, when GPIbb is defective (Trp21Stop, Ser23Stop,
allele also contained a frame-shift mutation, caused by the
and Ala80), the GPIX and GPIba glycoproteins are synthe-
deletion of the last two bases of the codon TAT for Tyr492.
sized but they are unable to form a complex [9, 32, 34]. This This second allele has been identified as the cause of the
confirms the role of GPIbb in the correct assembly and Bernard Soulier syndrome in patients of northern European
stability of the GPIb-IX complex on the platelet surface. ancestry based on patients’ haplotype of polymorphic mar-
Several BSS mutations lead to deficient GPIba expression on kers [43].
the platelets surface of patients.
In a GPIbb gene, the first compound heterozygote reported
described a Japanese case presenting two mutations at
BERNARD SOULIER SYNDROME (BSS) residues 88 and 108 of the GPIbb protein. This patient
MUTATIONS presented a variant of the BSS phenotype in which neither
Until 2006, 47 different genetic defects associated with BSS thrombocytopenia nor a bleeding tendency was observed
have been identified: 20 mutations in GPIba, 16 mutations in [44]. The second interesting example concerned another
GPIbb, and 11 in GPIX [13]. Recently, several novel mutations Japanese boy presenting two independent heterozygous
have been described (see Table 1). mutations in the GPIbb gene: Cys122Ser and 1096delG
[45]. The third case is identified in a Tunisian patient having
Five mutations in GPIba, with Ser23Stop mutation in GPIbb gene in a heterozygous state
. Three frameshift: C3221 insertion [35]; TGAG dele- and two other missense heterozygote mutations in the same
tion starting from the last base of the codon for Ser23 gene: (Asp 51 Gly) and (Ala 55 Pro). The last case is the only
[36] and TTCACATG deletion at positions 1136_1143 report of BSS showing compound heterozygosity for three
[37]. mutations in the same gene [39].
. Homozygous missense mutation: Trp207Gly [38]. The compound heterozygosity is also observed in a patient
. Heterozygous missense mutation: Asn41His [54]. 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
Two mutations in GPIbb: with a single heterozygous missense mutation at GPIba gene
. A nonsense mutation Ser23Stop [34]. has been described. The mutation converts Tyr to Asp at
. Compound heterozygous for Ser23Stop, Asp51Gly, residue 54 in the second leucine-rich repeat. This patient was
and Ala55Pro [39]. initially diagnosed with idiopathic thrombocytopenic purpura
[48]. BSS rarely has been reported with deletion in the
This raises the number of reported mutations to 54 DiGeorge/Velo-cardio-facial chromosomal region in 22q11.2,
(Table 1). We note that there is no hot spot mutation. so the GPIbb mutation is found on only one allele while the
Molecular defects can be classified as follows: other is deleted [49]. Genetic changes described in the BSS
patients may directly affect the vWF binding site on GPIba,
. Missense mutations or short in-frame deletions that inhibit the association of GPIb and GPIX following protein
give rise to normal or a slightly modified protein synthesis, or affect posttranslational modifications that may
leading to a dysfunctional receptor or to an abnormal influence the function of the complex [2, 23]. No significant
complex with decreased surface expression. relationship was found between the type of mutation, the
. Nonsense mutations giving rise to shorter proteins. defective gene responsible of the phenotype, and the clinical
. Insertions or deletions leading to a frame shift, a novel observations of patients. All of them suffered from hemor-
polypeptide sequence or a premature Stop [40]. rhagic symptoms.
. Compound heterozygosity has also been reported in
BSS patients.
FOUNDER MUTATIONS
In GPIba, two compound heterozygote BSS patients have Some BSS mutations have been described in several families
been described with a maternal allele with a T insertion at 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]Arg2AA]Stop Lanza [13]
^Ser39Glu4051AA]Stop Lanza [13]
Arg76]Leu19AA]Stop Lanza [13]
Val295]Gly39AA]Stop Lanza [13]
Ser444]Ile11AA-Stop (het) Lanza [13]
Thr452]Pro58AA]Stop Lanza [13]
Tyr492]Cys80AAStop 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]SerDi 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 ]Ala86AA]Stop Di George- Lanza [13]
VCF
^13bp Signal sequence22AA]Stop Lanza [13]
Ala131]Gly 153AA]Stop Lanza [13]
Promoter Mutation GATADi 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 cluded that patients, initially diagnosed to have autosomal
families [50], two Finnish families [51], and two other dominant macrothrombocytopenia, are in reality heterozy-
African-American families [11]. Phe55Ser missense mutation gous BSS [3].
in GPIX was revealed in two families from south Iran [35].
The Asn45Ser mutation in the GPIX gene has been
In GPIbb, the Tyr88Cys mutation was found in several
described in about 10 unrelated families of different origins:
Japanese families [52], a 13-bp deletion of the signal peptide
Finnish, British, Austrian, Swedish, Belgian, and Turkish.
coding sequence leading to premature termination found in
This gene defect is considered the most often identified
two related Japanese families [53] and in one patient from
molecular defect causing BSS in Caucasians. Koskela et al [51]
Saudi Arabia [40]. Similarly, the Ala156Val mutation was
identified in several families with the heterozygous BSS suggested that this mutation appears to be an ancient
phenotype [3]. mutation shared by northern and central European popula-
tions and proposed that Asn45Ser genotyping would be
Recently, we reported the occurrence of Ser23Stop mutation helpful for a differential diagnosis. Interestingly, thanks to
in GPIbb in three unrelated Tunisian families and we this mutation, doctors who misdiagnosed three unrelated
suggested that this mutation is founder in the Tunisian German patients with immune thrombocytopenia, corrected
population [39]. To identify the molecular basis of 12
the diagnosis after sequencing the three candidate’s genes for
Italian families having a form of autosomal dominant
BSS and they revealed the presence of Asn45Ser mutation in
macrothrombocytopenia, Savoia et al [3] have used a linkage
GPIX [14].
analysis, mutation screening, and flow cytometry. Linkage
analysis in two large families localized the candidate gene to Heterozygous carriers of the bleeding disorder Bernard
chromosome 17p, precisely the GPIba. In six families, they Soulier syndrome are occasionally identified as isolated cases
revealed the presence of a missense mutation (Ala156Val) of giant platelet disorder/macrothrombocytopenia or mis-
with a reduction of the platelets glycoprotein expression as diagnosed with idiopathic thrombocytopenic purpura (ITP),
observed in the heterozygous BSS patients. Authors con- 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 involved in the sulfation of tyrosines 276, 278 and 279. Blood.
2002;99(12):44224427.
inappropriate therapy.
20. Li CQ, Dong JF, López JA. The mucin-like macroglycolpeptide region of
Disclosure: The author/authors declares/declare no conflict of glycoprotein Ib alpha is required for cell adhesion to immobilized von
interest. Willebrand factor (vWF) under flow but not for static vWF binding.
Thromb Haemost. 2002;88(4):673677.
Funding: The authors have received support from the Tunisian 21. Kenny D, Morateck PA, Montgomery RR. The cysteine knot of platelet
Government to conduct this study. glycoprotein Ib beta (GPIb beta) is critical for the interaction of GPIb beta
with GPIX. Blood. 2002;99(12):44284433.
Acknowledgement: We deeply thank Khmaied Benhaj for reading 22. Bodnar RJ, Xi X, Li Z, Berndt MC, Du X. Regulation of glycoprotein Ib-IX-
the manuscript. Von Willebrand factor interaction by c-AMP-dependant protein kinase-
mediated phosphorylation at Ser166 of glycoprotein Iba. J Biol Chem.
2002;277(49):4708047087.
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