Variant Bernard-Soulier syndrome type bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex.

Abstract

Introduction We have studied a patient with a congenital bleeding disorder and phenotypic manifestations typical of Bernard-Soulier syndrome, including giant platelets with absent ristocetin-induced von Willebrand factor binding. Two monoclonal antibodies reacting with distinct epitopes in the amino-terminal domain of the a-chain of glycoprotein (GP) Ib were used to estimate the number of GP Ib molecules on the platelet membrane. In the patient, binding of one antibody (LJ-TblO) was 50% of normal, while binding of the other (LJ-Ibl) was absent. Binding of both antibodies was reduced to -50% of normal in the mother and one sister of the propositus, and their platelets exhibited -70% of normal von Willebrand factor binding. Immunoblotting studies confirmed the presence of GP Iba, as well as GP IX, in patient platelets. Antibody LJ-Ib10, but not LJ-Ibl, could immunoprecipitate the patient's GP Iba from surfacelabeled proteins. Thus, platelets from the propositus contained a structurally and functionally altered GP Ib-IX complex lacking a specific antibody epitope and the ability to bind von Willebrand factor. In contrast, the binding of human a-thrombin to the patient's platelets was normal, and three classes of binding sites with high, intermediate, and low affinity could be detected. These studies define a distinct variant form of BernardSoulier syndrome and provide evidence, based on a naturally occurring mutant molecule, that the amino-terminal region of GP Iba contains a von Wiliebrand factor-binding domain distinct from the high affinity thrombin-binding site. Use of different monoclonal antibodies with distinct epitope specificities appears to be essential for a correct identification of variant Bernard-Soulier syndrome. (J. Clin. Invest. 1990. 86:25-31.)

Point mutation in a leucine-rich repeat of platelet glycoprotein Ib alpha resulting in the Bernard-Soulier syndrome.

“…In contrast to the classical form of the disease, a previously characterized variant ofBernard-Soulier syndrome, designated type Bolzano, was found to express a dysfunctional GP Ib-IX-V complex on the surface of giant platelets that lacked the ability to bind vWF ( 13). In this report we demonstrate that the latter abnormality is caused by an Ala'56 -.…”

“…Among the reported cases of Bernard-Soulier syndrome, however, type Bolzano represents a unique example since the GP lb-IX-V complex is present on the platelet surface, albeit with a reduced number of copies, but is dysfunctional, showing normal ability to bind a-thrombin but defective vWF binding function ( 13 ). In previous studies ( 13), we suggested that the genetic defect resulting in the type Bolzano phenotype was likely to be localized in the a-subunit of GP lb for two reasons: (a) vWF binding to the receptor, the function defective in platelets from the propositus, is an intrinsic property of the amino terminus of GP Iba (21,22); and (b) immunological characterization of the propositus' platelets demonstrated loss ofthe epitope recognized by the monoclonal antibody LJ-Ib 1, located within residues 1-293 of the GP Iba-chain (20).…”

“…The propositus was previously described as a typical case of Bernard-Soulier syndrome, with giant platelets exhibiting a markedly decreased vWF-binding capacity ( 1 3, 15). Detailed immunochemical studies revealed also a major structural abnormality ofGP Iba characterized by the absence ofconformation-dependent epitopes recognized by specific monoclonal antibodies ( 13).…”

A A386G biallelic GPIb gene mutation with anomalous behavior: a new mechanism suggested for Bernard-Soulier syndrome pathogenesis

“…7 DNA extraction, amplification and sequencing of the GPIbα gene were performed as explained elsewhere, 6 using the primer sets published by Savoia et al 12 Platelet lysate analysis by Western blot (WB) was carried out as previously described. 7 The features of the mAbs used for flow cytometry and WB 13 are available in the Online Supplementary Appendix, along with details of cDNA analysis.…”

Novel point mutation in a leucine-rich repeat of the GPIb chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant

“…5 Although in most cases the molecular defect remains unknown, a significant percentage of these patients have recently been recognized in Italy as being affected by the Bolzano Bernard-Soulier syndrome (BSS) variant, which is characterized by Ala156Val substitution in the GPIbα protein 6 near the anionic sulfated region of the last leucine-rich repeat (LRR). 7,8 Most of the causative mutations in BSS affect the GPIbα subunit of the platelet membrane glycoprotein Ib/IX/V complex, 9,10 so we performed sequencing analyses on the GPIbα gene in the affected members of two families who had previously been classified as CHMT. The study revealed a new mutation in the first LRR motif in the N-terminal domain of GPIbα, where asparagine 41 (one of the best-conserved residues of the LRR consensus sequence) was substituted by a histidine (N41H mutation).…”