Molecular basis of Bernard–Soulier syndrome in 27 patients from India

Abstract

To cite this article: Sumitha E, Jayandharan GR, David S, Jacob RR, Sankari Devi G, Bargavi B, Shenbagapriya S, Nair SC, Abraham A, George B, Viswabandya A, Mathews V, Chandy M, Srivastava A. Molecular basis of Bernard–Soulier syndrome in 27 patients from India. J Thromb Haemost 2011; 9: 1590–8. Summary. Background: Bernard–Soulier syndrome (BSS) is an extremely rare (1:1 million) bleeding disorder of platelet adhesion, caused by defects in the glycoprotein (GP)Ib/IX/V complex. Patients and methods: The diagnosis in 27 patients was based on low platelet count, presence of giant platelets and aggregometry studies. Flow cytometry to assess the surface GPIb/IX/V complex showed reduced (7.7–57%) expression. gDNA was screened for mutations in the GPIBA, GPIBB, GP9 genes using PCR‐conformation sensitive gel electrophoresis (CSGE). Results: Thirteen different disease‐causing mutations, including missense (54%), frameshifts (38%) and nonsense (8%) mutations, were identified in 27 patients. Eleven of them were novel including five novel frameshifts (GPIbα: p.Gln97_98fsX113, p.Pro402_403fsX52; GPIbβ: p.Arg17fsX14; GPIX: p.Gly24fsX43, p. Pro130fs, a nonsense mutation (GPIX, p.94, Gln>X) and five novel missense mutations (GPIbα: p.492, Tyr>His; GPIbβ: p.65, Pro>Arg, p.129, Gln>His, p.132, Leu>Pro; GPIX: p.55, Phe>Cys). Interestingly, four common mutations, Cys8Arg (n = 6) and Phe55Ser (n = 2), Phe55Cys (n = 2) in GPIX and a novel 22‐bp deletion in the GPIBB gene predicting p.Arg17fsX 14 (n = 10) were seen in 20 patients. Conclusion: The molecular data presented here is the largest series of BSS patients to be reported so far, adding significantly to the mutation database of this condition and also useful for its genetic diagnosis in India.

Molecular pathology of Bernard–Soulier syndrome in Indian patients

“…p.Met338fsX13 (BSS3.01). Two mutations reported earlier [13,14] were also detected, one insertion of a single base T at position 1455 in GPIb gene, i.e. p.Val485fsX13 (BSS7.01) and one missense change in GPIX gene, i.e.…”

“…Substitution of cysteine residue with a large molecule like arginine is also known to destabilize the fold. This is also a common mutation reported in South Indian patients and other earlier reports [14] and has been known to have mild clinical manifestations.…”

Novel mutation in the glycoprotein Ibβ in a patient with Bernard–Soulier syndrome

“…To date, about 60 genetic abnormalities including missense, nonsense, and deletion mutations in the GPIba, GPIbb, and GPIX genes have been associated with BSS [7][8][9]. In this study, we report on a novel genetic alteration of the GPIbb gene (c.423C > A) in a patient with BSS.…”

“…So far, about 60 genetic abnormalities have been described in the genes GPIba, GPIbb, and GPIX [7][8][9], whereas no mutation has been found in the gene for GPV [4]. In this report, we present a case of BSS in a 14-month-old boy caused by a novel genetic mutation.…”

A Case Report of Bernard-Soulier Syndrome in Differential Diagnosis of Immune Thrombocytopenic Purpura.

“…They found out a patient from a consanguineous family with severe bleeding episodes, thrombocytopenia and very large platelets [1]. It is a rare hereditary disorder (1:1000000) [2].…”