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Bernard Soulier Syndrome a Rare Bleeding Disorder With a Wide Range of Genetic Defects

Bernard Soulier Syndrome a Rare Bleeding Disorder With a Wide Range of Genetic Defects

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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 Genetique Moleculaire des Eucaryotes, Centre de Biotechnologie de Sfax, BP‘‘K’’3038, Sfax, Tunisia and 2Centre Regional 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)IbIX-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, macrothrombocytopenia, 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 Genetique Moleculaire 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 hemorrhagiparous 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
JCD 2010; 000:(000). Month 2010 1

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 thrombocytopenia. Patients with increased platelet size can be classified in several forms of inherited macrothrombocytopenia such as BSS, May-Hegglin anomaly, gray platelet syndrome, von Willebrand disease, Montreal platelet syndrome, 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 2Á3 mm), prolonged skin bleeding time (15 min) and thrombocytopenia (between 1010 to 1011 platelets/l compared to 1.5)1011
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domain to a platelet plasma membrane. the complex facilitates the ability of thrombin at low concentrations to activate platelets [2. 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]. GPIba. and in menses. many patients had been erroneously diagnosed with immune thrombocytopenia and were treated with steroids without response [14]. 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. Based only on clinical manifestations. This globular domain contains both the vWF binding site and thrombin binding site. 15]. This kinase negatively regulates vWF fixation on the GPIb-IX-V complex [22]. they present reduced or absent ristocetin-induced platelet aggregation. 13]. The GPIX gene is composed by three exons (72.2. normally expressed on the platelets surface of healthy persons and BSS patients. This protein also includes a transmembrane domain with a single leucine-rich repeat motif and a short cytoplasmic tail. 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. 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 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. collagen. The GPV contains an extra cellular domain with 15 leucinerich repeats and 8 glycosylation sites [24]. phosphorylated at Ser166 by the PKA (Protein Kinase AMPc dependant).Journal of Coagulation Disorders to 4)1011 platelets/l in healthy persons). serves as a positive control.com . Clinical manifestations appear from childhood and usually include frequent episodes of epistaxis. arachidonic acid. Molecular characterization of the four genes involved in the complex shows common structural features despite their different chromosomal locations. the integrity of which region is essential to provide a normal function of the GPIb-IX-V complex [17]. While the platelets of patients aggregate normally in response to agonists such as adenosine diphosphate (ADP). The GPIb consists of two disulfide linked subunits. Approximately 160 min are required for the complex to be fully processed and to appear on the plasma membrane. all BSS patients have decreased or absent expression of the GPIb-IX-V glycoproteins. The largest glycoprotein. The GPIba protein also contains a highly O-glycosylated macroglycopeptide mucin core that resembles a stem connecting the N-terminal JCD 2010. and Tyr 279 also [18]. platelets cannot adhere to vascular subendothelium under high shear stress. the open reading frame (ORF) begins in the first exon and finishes in the second one [31]. 000:(000). or gingival bleeding [2]. Those specialized laboratory tests are essential to avoid confusion between BSS and other platelet disorders such as May-Hegglin or idiopathic thrombocytopenic purpura [2. menorrhagia. Severe bleeding occurred in the case of trauma. In addition. GPIba (145 kD) and GPIbb (22 kD) while GPIX (20 kD) and GPV (82 kD) bind to GPIb noncovalently [2]. 20]. contain their entire coding region within one exon. Over 60% of GPIba are degraded by lysosomes when expressed only with GPIbb or GPIX. This glycoprotein is essential for the correct assembly of the GPIbIX-V complex on a platelet membrane [23]. purpura. The GPIIb-IIIa complex. which is essential for interaction with GPIX [21]. It contains three sulfated tyrosins Tyr 276. 126. a single transmembrane sequence. Month 2010 2 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. The complex is then transported into the Golgi cisternae to be modified [23]. The GPIX has only one leucine-rich repeat motif. epinephrine. 12]. GPIbb on 22q11. Some patients can show gastrointestinal hemorrhage. surgical intervention. Note that in the absence of a functioning vWF receptor. 11. and GPV on 3q29 [27Á30]. The complex is expressed at a high density on the cell surface (24. and a cytoplasmic tail [2. consists of a N-terminal globular domain that contains seven tandem leucine-rich repeats. Pregnancy in BSS patients may present complications of varying severity [10]. with the exception of GPIbb. GPIX on 3q21. In addition. Tyr 278. and www. a transmembrane domain and a short cytoplasmic tail. The tyrosine sulfation constitutes a posttranslational modification indispensable to ensure interaction with the vWF [19]. GPV is essential to bind thrombin with high affinity [23].000 copies/platelet) [16]. All four genes are relatively devoid of introns and. GPIbb gene contains two exons (36 bp and 918 bp) separated by one intron (274 bp). About 25% of GPIba expressed on incomplete GPIb-IX or GPIb-IX-V complexes are degraded through a nonlysosomal pathway. 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. The GPIbb protein has a N-terminal extra cellular domain that contains a cysteine knot region.slm-hematology. Chronic easy bruising and frequent hematomas are rarely reported [9]. a cleavage site by thrombin in the amino terminal transmembrane domain and a short intracellular tail [25]. The absence of either GPIbb or GPIX increased the rate of GPIba degradation [23]. 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.

BSS rarely has been reported with deletion in the DiGeorge/Velo-cardio-facial chromosomal region in 22q11. Two mutations in GPIbb: . Heterozygous missense mutation: Asn41His [54]. In GPIba. The mutation converts Tyr to Asp at residue 54 in the second leucine-rich repeat. a novel polypeptide sequence or a premature Stop [40]. 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]. For example. . TGAG deletion starting from the last base of the codon for Ser23 [36] and TTCACATG deletion at positions 1136_1143 [37]. We note that there is no hot spot mutation. Compound heterozygosity has also been reported in BSS patients. 000:(000). Ser23Stop. . 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). 34]. 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). Asp51Gly. Homozygous missense mutation: Trp207Gly [38]. The second interesting example concerned another Japanese boy presenting two independent heterozygous mutations in the GPIbb gene: Cys122Ser and 1096delG [45].com 3 FOUNDER MUTATIONS Some BSS mutations have been described in several families from different nationalities or in one given population. the GPIX and GPIba glycoproteins are synthesized but they are unable to form a complex [9. GPIbb. inhibit the association of GPIb and GPIX following protein synthesis. the defective gene responsible of the phenotype. Bernard Soulier patients and the transfection of heterologous cells have indicated that GPIba. 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. The last case is the only report of BSS showing compound heterozygosity for three mutations in the same gene [39]. This confirms the role of GPIbb in the correct assembly and stability of the GPIb-IX complex on the platelet surface. and GPIX. Molecular investigations of numerous BSS patients showed that only three genes are responsible of the disease: GPIba. No significant relationship was found between the type of mutation. causing a frame shift that yielded a stretch of 51 amino acids before a premature stop codon. 33]. 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 markers [43]. . This has important implications in pathology.slm-hematology. 47 different genetic defects associated with BSS have been identified: 20 mutations in GPIba. and a paternal allele with a T715A substitution changing Cys209 to Ser [41]. Five mutations in GPIba. 47]. and the clinical observations of patients. 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. respectively) and two introns with the ORF contained in the third exon [24]. with . Several BSS mutations lead to deficient GPIba expression on the platelets surface of patients. 32. so the GPIbb mutation is found on only one allele while the other is deleted [49].Bernard Soulier syndrome with wide range of genetic defects 675 pb.2. Genetic changes described in the BSS patients may directly affect the vWF binding site on GPIba. Three frameshift: C3221 insertion [35]. position 1418 causing a translational frameshift and premature polypeptide termination. . All of them suffered from hemorrhagic symptoms. Recently. The second allele also contained a frame-shift mutation. Insertions or deletions leading to a frame shift. Compound heterozygous for Ser23Stop. The modification of a single constituent will affect expression of the entire complex. caused by the deletion of the last two bases of the codon TAT for Tyr492. several novel mutations have been described (see Table 1). BERNARD SOULIER SYNDROME (BSS) MUTATIONS Until 2006. Month 2010 . This raises the number of reported mutations to 54 (Table 1). and Ala80). the first compound heterozygote reported described a Japanese case presenting two mutations at residues 88 and 108 of the GPIbb protein. 23]. and 11 in GPIX [13]. two compound heterozygote BSS patients have been described with a maternal allele with a T insertion at www. 16 mutations in GPIbb. The BSS patient with two homozygous mutations in GPIba has also been described. This patient was initially diagnosed with idiopathic thrombocytopenic purpura [48]. when GPIbb is defective (Trp21Stop. . In JCD 2010. and Ala55Pro [39]. . A nonsense mutation Ser23Stop [34]. and GPIX proteins are necessary for efficient expression of the complex whereas GPV is not essential [2. GPIbb. This patient presented a variant of the BSS phenotype in which neither thrombocytopenia nor a bleeding tendency was observed [44]. Molecular defects can be classified as follows: . No mutations have been reported within the GPV gene [32]. In a GPIbb gene. or affect posttranslational modifications that may influence the function of the complex [2. A BSS patient with a single heterozygous missense mutation at GPIba gene has been described. Nonsense mutations giving rise to shorter proteins.

000:(000).slm-hematology. Update of BSS Mutations Described in the Three Genes GPIba. and GPIX Missense mutations or Gene short deletions GPIba Tyr54]Asp (het) (macrothrombocytopenia) Leu57]Phe Cys65]Arg Leu123]Pro Leu126]Phe Leu129]Pro Ala156]Val ^Leu179 ^169-180/Glu81]Lys Cys 209]Ser Asn41His (het) Trp207Gly ^ TGAG starting from the last base of the codon Ser23 ^ 1136 1143 Trp343] Stop Ser444] Stop Trp498] Stop Lys19]Arg'2AA]Stop ^Ser39Glu40'51AA]Stop Arg76]Leu'19AA]Stop Val295]Gly'39AA]Stop Ser444]Ile'11AA-Stop (het) Thr452]Pro'58AA]Stop Tyr492]Cys'80AAStop C3221 insertion GPIbb Cys5]Tyr Arg17]Cys(Giant platelets) Pro29]Leu (het) Asn64]Thr Pro74]Arg Tyr88]Cys Tyr88]Cys 'Ala108-Pro (het) (Giant platelets) Pro96]Ser'Di George-VCF Cys122]Ser (het) Trp21]Stop Cys116] Stop Trp123] Stop Nonsense mutations Frameshift]Stop Other References Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Vettore et al [54] Rosenberg et al [38] Vettore et al [36] Imai et al [37] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Afrasiabi et al [35] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Á JCD 2010.Journal of Coagulation Disorders Table 1.com . GPIBb. Month 2010 4 www.

000:(000). and Turkish. Koskela et al [51] suggested that this mutation appears to be an ancient mutation shared by northern and central European populations and proposed that Asn45Ser genotyping would be helpful for a differential diagnosis. Phe55Ser missense mutation in GPIX was revealed in two families from south Iran [35]. Recently. British. In GPIbb. GPIba. This gene defect is considered the most often identified molecular defect causing BSS in Caucasians. corrected the diagnosis after sequencing the three candidate’s genes for BSS and they revealed the presence of Asn45Ser mutation in GPIX [14]. Austrian. and flow cytometry. The Asn45Ser mutation in the GPIX gene has been described in about 10 unrelated families of different origins: Finnish. mutation screening. Di George-VCF: Di George (Velo-Cardio-Facial syndrome) deletion of chromosome region 22q11. 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]. Giant platelets: variant phenotype not a BSS. Savoia et al [3] have used a linkage analysis. Swedish.slm-hematology. Heterozygous carriers of the bleeding disorder Bernard Soulier syndrome are occasionally identified as isolated cases of giant platelet disorder/macrothrombocytopenia or misdiagnosed with idiopathic thrombocytopenic purpura (ITP).2 on the second allele.com 5 cluded that patients. two Finnish families [51]. Numbering is based on the mature sequence (GPIX Leu((10) ]Pro is located in the signal peptide). and two other African-American families [11]. Belgian. amino acids (AA) are in three letter code. (]) change from wild type to mutated AA sequence. initially diagnosed to have autosomal dominant macrothrombocytopenia. 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]. all new mutations are indicated in bold. Similarly. To identify the molecular basis of 12 Italian families having a form of autosomal dominant macrothrombocytopenia. Interestingly. are in reality heterozygous BSS [3]. they revealed the presence of a missense mutation (Ala156Val) with a reduction of the platelets glycoprotein expression as observed in the heterozygous BSS patients. which is why the identification of founder mutations is very JCD 2010. Leu129Pro was identified in two Afro-American families [50]. Linkage analysis in two large families localized the candidate gene to chromosome 17p. the Ala156Val mutation was identified in several families with the heterozygous BSS phenotype [3]. (het): compound heterozygote. doctors who misdiagnosed three unrelated German patients with immune thrombocytopenia. With ^: deletion. the Tyr88Cys mutation was found in several Japanese families [52]. precisely the GPIba.Bernard Soulier syndrome with wide range of genetic defects Table 1 (Continued) Missense mutations or Gene short deletions Nonsense mutations Ser23Stop Gly81 ]Ala'86AA]Stop 'Di GeorgeVCF ^13bp Signal sequence'22AA]Stop Ala131]Gly '153AA]Stop Promoter Mutation GATA'Di George-VCF Ser23Stop Asp51Gly and Ala55Pro (het) GPIX Leu((10)]Pro Cys8]Arg Asp21]Gly (het) Leu40]Pro Asn45]Ser (homo and het) Phe55]Ser Cys73]Tyr Asn86]Ala DArg87-Pro89 (het) Cys97]Tyr Ala140]Thr Trp127] Stop Frameshift]Stop Other References Hadjkacem et al [34] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Hadjkacem et al [39] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Lanza [13] Notes: Regarding the list of Lanza 2006. In six families. thanks to this mutation. Month 2010 . Authors conwww.

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