Spectrum of the Mutations in Bernard-Soulier Syndrome

• Published in: Human mutation Vol. 35; no. 9; pp. 1033 - 1045
• Main Authors: Savoia, Anna, Kunishima, Shinji, De Rocco, Daniela, Zieger, Barbara, Rand, Margaret L., Pujol-Moix, Nuria, Caliskan, Umran, Tokgoz, Huseyin, Pecci, Alessandro, Noris, Patrizia, Srivastava, Alok, Ward, Christopher, Morel-Kopp, Marie-Christine, Alessi, Marie-Christine, Bellucci, Sylvia, Beurrier, Philippe, de Maistre, Emmanuel, Favier, Rémi, Hézard, Nathalie, Hurtaud-Roux, Marie-Françoise, Latger-Cannard, Véronique, Lavenu-Bombled, Cécile, Proulle, Valérie, Meunier, Sandrine, Négrier, Claude, Nurden, Alan, Randrianaivo, Hanitra, Fabris, Fabrizio, Platokouki, Helen, Rosenberg, Nurit, HadjKacem, Basma, Heller, Paula G., Karimi, Mehran, Balduini, Carlo L., Pastore, Annalisa, Lanza, Francois
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.09.2014; John Wiley & Sons, Inc
• Subjects: Alleles; Bernard-Soulier syndrome; Bernard-Soulier Syndrome - diagnosis; Bernard-Soulier Syndrome - genetics; Databases, Nucleic Acid; Founder Effect; Genetic Variation; GP1BA; GP1BB; GP9; Humans; Mutation; Platelet Glycoprotein GPIb-IX Complex - genetics; Polymorphism, Single Nucleotide; von Willebrand Diseases - genetics; Web Browser; GP9; GP1BA; GP1BB; Bernard-Soulier syndrome
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.22607

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. We present a comprehensive spectrum of mutations of GP1BA (GPIbα), GP1BB (GPIbβ) and GP9 (GPIX) causing Bernard‐Soulier syndrome (BSS), a rare bleeding autosomal recessive disorder. Of the 211 families enrolled, 28% have mutations in GP1BA, another 28% in GP1BB and the remaining 44% in GP9. Excluding a few founder effects, most of the 112 different mutations identified are private. Missense variants, whose pathogenetic role should be determined through functional studies, accounts for more than half BSS alleles.