Spectrum of the Mutations in Bernard-Soulier Syndrome

Abstract

Bernard-Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder characterized by defects of the GPIb-IX-V complex, a platelet receptor for von Willebrand factor (VWF). Most of the mutations identified in the genes encoding for the GP1BA (GPIbα), GP1BB (GPIbβ), and GP9 (GPIX) subunits prevent expression of the complex at the platelet membrane or more rarely its interaction with VWF. As a consequence, platelets are unable to adhere to the vascular subendothelium and agglutinate in response to ristocetin. In order to collect information on BSS patients, we established an International Consortium for the study of BSS, allowing us to enrol and genotype 132 families (56 previously unreported). With 79 additional families for which molecular data were gleaned from the literature, the 211 families characterized so far have mutations in the GP1BA (28%), GP1BB (28%), or GP9 (44%) genes. There is a wide spectrum of mutations with 112 different variants, including 22 novel alterations. Consistent with the rarity of the disease, 85% of the probands carry homozygous mutations with evidence of founder effects in some geographical areas. This overview provides the first global picture of the molecular basis of BSS and will lead to improve patient diagnosis and management.

Linkage between the mechanisms of thrombocytopenia and thrombopoiesis

“…105 In addition, congenital deficiency in GPIb/IX/V, the platelet vWF receptor, results in Bernard-Soulier syndrome, a rare bleeding disorder that is accompanied by macrothrombocytopenia. 106 Loss of GPIb/IX/V from the platelet membrane disables platelets from adhering to the walls of injured vessels, thus patients suffer from bleeding problems. The cytoplasmic domain of GPIba associates with actin via filamin A.…”

The contribution of mouse models to the understanding of constitutional thrombocytopenia

“…The monoallelic form leads to a reduction of about 40% in expression of the GPIb-V-IX complex, and platelet function is little or not affected. 22 Whereas the absence of the GPIb-V-IX complex explains the functional defect in platelets, the mechanisms underlying the macrothrombocytopenia are not fully understood. Various BSS mouse models have been developed and have helped to explore potential mechanisms involving cytoskeletal proteins.…”

Does Bernard‐Soulier syndrome protect against thrombotic thrombocytopenic purpura?

“…BSS is usually an inherited autosomal recessive (rarely autosomal dominant) condition characterized by prolonged bleeding time and macrothrombocytopenia. [8][9][10] BSS is often associated with epistaxis, gingival and cutaneous bleeding, and hemorrhage following trauma. 8 BSS is caused by mutations in the GPIb-IX-V complex, which is encoded by four genes (GP1BA, GP1BB, GP9, and GP5).…”

“…8 The mutations are most common in GP9, but may also occur in GP1BA or GP1BB, but have not been reported in GP5. 10 This is because GP5 expression is not needed for expression of the other subunits of the GPIb-IX-V complex. 8 These mutations almost always result in either very low or undetectable levels of GPIb-IX-V. 8 An exception is the Bolzano variant of BSS, caused by an A156V mutation in GP1BA, in which platelets express GPIb-IX-V in normal levels, but are unable to bind vWF.…”

“…The incidence of BSS is estimated to be 1 in a million persons. 10 The incidence of TTP is estimated to be 3.7 in a million persons in the USA. 1 Thus, only 3.7 in a trillion persons are estimated to have both medical conditions.…”