Novel point mutation in the leucine‐rich motif of the platelet glycoprotein IX associated with Bernard‐Soulier syndrome

Suzuki, Keijiroh; Hayashi, Tomohiro; Yahagi, Akito; Akiba, Jiro; Tajima, Katsushi; Satoh, Shuichi; Sasaki, Hideo

doi:10.1046/j.1365-2141.1997.4753275.x

Cited by 27 publications

(18 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Samples in lanes N, 5 and 6 contain only the 211 bp fragment as expected for normal subjects (35 and 17 bp fragments are not detectable on 10% acrylamide gel); samples in lanes 1 and 2 contain two fragments of 71 and 140 bp as expected for subjects homozygous for the mutant allele; in lanes 3, 4 and 7 all the three fragments are present, indicating that these samples are from subjects heterozygous for the mutant allele. 1997; Clemetson et al, 1994;Noda et al, 1995Noda et al, , 1996Donner et al, 1996;Noris et al, 1997;Suzuki et al, 1997;Budarf et al, 1995;Ludlow, 1996); a qualitative defect of GPIba is often associated with the quantitative one (Ware et al, 1993;Margaglione et al, 1995). Mutations of the genes encoding for GPIba, GPIX and GPIbb may be responsible for this phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…1997; Clemetson et al, 1994;Noda et al, 1995Noda et al, , 1996Donner et al, 1996;Noris et al, 1997;Suzuki et al, 1997;Budarf et al, 1995;Ludlow, 1996); a qualitative defect of GPIba is often associated with the quantitative one (Ware et al, 1993;Margaglione et al, 1995). Mutations of the genes encoding for GPIba, GPIX and GPIbb may be responsible for this phenotype.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Noris

Arbustini

Spedini³

et al. 1998

Br J Haematol

View full text Add to dashboard Cite

Summary.We describe a new variant of Bernard-Soulier syndrome characterized by almost normal amounts of GPIb and severely reduced GPIX and GPV. Despite surface expression, GPIba failed to support ristocetin-induced platelet agglutination and to bind two conformationdependent monoclonal antibodies, suggesting a qualitative defect. Sequence analysis of the gene coding for GPIX revealed a T-to-C substitution at base 1811, leading to a Leu40Pro conversion, whereas no defects were found in the coding region of the GPIba gene. Allele-specific restriction enzyme analysis showed that the propositus and one of his sisters, both with severe bleeding diathesis, were homozygous for the GPIX mutation; the members of the family with mild bleeding diathesis and/or giant platelets in the peripheral blood were heterozygous, whereas the healthy ones were homozygous for the normal allele.Infusion of 1-desamino-8-D-arginine vasopressin normalized bleeding time in the two severely affected patients, although it did not modify ristocetin-induced platelet agglutination or membrane expression of GPIba, GPIX, GPIIb-IIIa and GMP-140. Moreover, in one patient, normalization of bleeding time and rise of von Willebrand factor plasma concentration did not seem to be directly related.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Noris

Arbustini

Spedini³

et al. 1998

Br J Haematol

View full text Add to dashboard Cite

show abstract

“…Consistent with our data, the cases previously reported to have the same mutations as in this group (p.Cys225Ser of GP1BA and p.Phe71Ser of GP9) were associated with a severe phenotype. 21,25,27 The other half of patients had a mild bleeding tendency (grade 2) without any additional manifestations to petechiae, ecchymoses, epistaxis and gum bleeding, which did not necessitate any particular interventions. These patients had mutations of the GP9 gene affecting residue 24 (p.Cys24Arg and p.Cys24Trp) in 5 cases or residue 95 (p.Tyr95Cys) in one case.…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Savoia¹,

Pastore²,

Rocco³

et al. 2010

Haematologica

View full text Add to dashboard Cite

The online version of this article has a Supplementary Appendix. BackgroundBernard-Soulier syndrome is a severe bleeding disease due to a defect of GPIb/IX/V, a platelet complex that binds the von Willebrand factor. Due to the rarity of the disease, there are reports only on a few cases compromising any attempt to establish correlations between genotype and phenotype. In order to identify any associations, we describe the largest case series ever reported, which was evaluated systematically at the same center. Design and MethodsThirteen patients with the disease and seven obligate carriers were enrolled. We collected clinical aspects and determined platelet features, including number and size, expression of membrane glycoproteins, and ristocetin induced platelet aggregation. Mutations were identified by direct sequencing of the GP1BA, GP1BB, and GP9 genes and their effect was shown by molecular modeling analyses. ResultsPatients all had a moderate thrombocytopenia with giant platelets and a bleeding tendency whose severity varied among individuals. Consistent with expression levels of GPIbα always lower than 10% of control values, platelet aggregation was absent or severely reduced. Homozygous mutations were identified in the GP1BA, GP1BB and GP9 genes; six were novel alterations expected to destabilize the conformation of the respective protein. Except for obligate carriers of a GP9 mutation with a reduced GPIb/IX/V expression and defective aggregation, all the other carriers had no obvious anomalies. ConclusionsRegardless of mutations identified, the patients' bleeding diathesis did not correlate with thrombocytopenia, which was always moderate, and platelet GPIbα expression, which was always severely impaired. Obligate carriers had features similar to controls though their GPIb/IX/V expression showed discrepancies. Aware of the limitations of our cohort, we cannot define any correlations. However, further investigations should be encouraged to better understand the causes of this rare and underestimated disease.Key words: Bernard-Soulier syndrome, macrothrombocytopenia, GP1BA, GP1BB and GP9 mutations. Citation: Savoia

show abstract

“…14 In support of this notion, several mutations in the LRR domain of GPIb␣, GPIb␤, and GPIX result in loss of GPIb function and the development of BSS. [17][18][19][20][21] Folding, assembly, and maturation of the GPIb-IX complex begins in the ER, where it undergoes both N-linked and O-linked glycosylation before reaching the plasma membrane. 22 Lack of the GPIb␣, GPIb␤, or GPIX subunit results in the abnormal processing, assembly, and cell-surface expression of the GPIb-IX complex.…”

mentioning

confidence: 99%

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

Staron

Hong

et al. 2011

Blood

View full text Add to dashboard Cite

The platelet glycoprotein Ib-IX-V complex (GPIb-IX-IV) is the receptor for VWF and is responsible for VWF-mediated platelet activation and aggregation. Loss of the GPIb-IX-V complex is pathogenic for Bernard-soulier Syndrome (BSS), which is characterized by macrothrombocytopenia and impaired platelet function. It remains unclear how the GPIb-IX-V complex is assembled and whether there is a role for a specific molecular chaperone in the process. In the present study, we report that the assembly of the GPIb-IX-V complex depends critically on a molecular chaperone in the endoplasmic reticulum (ER): gp96 (also known as grp94 and HSP90b1). gp96/grp94 deletion in the murine hematopoietic system results in thrombocytopenia, prolonged bleeding time, and giant platelets that are clinically indistinguishable from human BSS. Loss of gp96/grp94 in vivo and in vitro leads to the concomitant reduction in GPIb-IX complex expression due to ER-associated degradation. We further demonstrate that gp96/grp94 binds selectively to the GPIX subunit, but not to gpIb␣ or gpIb␤. Therefore, we identify the platelet GPIX subunit of the GPIb-IX-V complex as an obligate and novel client of gp96/grp94. (Blood. 2011;117(26):7136-7144) IntroductionThe molecular chaperone gp96, 1 which is also known as grp94 2 or HSP90b1, is the paralog of heat-shock protein 90 (HSP90) in the endoplasmic reticulum (ER). Like other HSPs, gp96/grp94 is induced by the accumulation of misfolded proteins. 3 gp96/grp94 binds and hydrolyzes ATP, 4-6 is the most abundant protein in the ER lumen, and is ubiquitously expressed in all nucleated cells. Genetic studies have begun to clarify and expand the role of gp96/grp94 as the critical chaperone for multiple TLRs and integrins [7][8][9][10][11] and in the unfolded protein response (UPR). 12 Without gp96/grp94, the majority of integrins and TLRs are unable to fold properly and thus fail to exit the ER to traffic to the proper post-ER compartment. Using a Cre/loxP-mediated conditional deletion of gp96/grp94 in mice, we recently discovered that gp96/grp94 selectively regulates lymphopoiesis but not myelopoiesis. 10 However, it remains unclear whether gp96/grp94 chaperones other, as-yet-unidentified client proteins in the hematopoietic system.The platelet glycoprotein Ib-IX-V (GPIb-IX-V) complex consists of 4 transmembrane proteins: GPIb␣, GPIb␤, GPIX, and GPV 13 and functions as a receptor for VWF for platelet activation. 14 Defects in the biogenesis of this complex result in BSS. At the molecular and structural level, GPIb␣ and GPIb␤ are covalently linked by a disulfide bond; these proteins are noncovalently associated with GPIX and GPV. 13,15 The GPIb-IX complex belongs to proteins of the leucine-rich repeat (LRR) family. 16 Like other LRR-motif-containing proteins, GPIb␣ adopts a "horseshoe-like" shape that is thought to be involved in intermolecular interactions and ligand binding. 14 In support of this notion, several mutations in the LRR domain of GPIb␣, GPIb␤, and GPIX result in loss of GPIb function and the developm...

show abstract

Novel point mutation in the leucine‐rich motif of the platelet glycoprotein IX associated with Bernard‐Soulier syndrome

Cited by 27 publications

References 32 publications

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

A new variant of Bernard‐Soulier syndrome characterized by dysfunctional glycoprotein (GP) Ib and severely reduced amounts of GPIX and GPV

Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations

Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex

Contact Info

Product

Resources

About