Diversity of Glanzmann thrombasthenia in southern India: 10 novel mutations identified among 15 unrelated patients

• Published in: Journal of thrombosis and haemostasis Vol. 4; no. 8; pp. 1730 - 1737
• Main Authors: NELSON, E. J. R., NAIR, S. C., PERETZ, H., COLLER, B. S., SELIGSOHN, U., CHANDY, M., SRIVASTAVA, A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2006
• Subjects: Adolescent; Adult; Binding Sites; Blood Platelets - metabolism; Cell Membrane - metabolism; Child; DNA Mutational Analysis; Female; Fibrinogen - biosynthesis; Glanzmann thrombasthenia; Humans; Male; Mutation; mutations; Platelet Glycoprotein GPIIb-IIIa Complex - genetics; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; polymorphisms; Thrombasthenia - diagnosis; Thrombasthenia - genetics; αIIbβ3
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2006.02066.x

Background: Glanzmann thrombasthenia (GT) is a congenital bleeding disorder caused by either a lack or dysfunction of the platelet integrin αIIbβ3. Objectives: To determine the molecular basis of GT in patients from southern India. Patients: Fifteen unrelated patients whose diagnosis was consistent with GT were evaluated. Results: Platelet surface expression of αIIbβ3 was < 10%, 10%–50%, and > 50% of controls in five, nine, and one patient(s), respectively. Immunoblotting of the platelet lysates showed no αIIb in 14 patients, and no β3 in 10 patients, although severely reduced in four patients. Platelet fibrinogen was undetectable in 13 patients, and severely reduced in one patient. One patient showed normal surface αIIbβ3 expression, and normal αIIb, β3 and fibrinogen levels in the lysate. Ten novel candidate disease‐causing mutations were identified in 11 patients. The missense mutations included Gly128Ser, Ser287Leu, Gly357Ser, Arg520Trp, Leu799Arg in αIIb, and Cys575Gly in β3. We have already shown that Gly128Ser, Ser287Leu, and Gly357Ser mutations variably affect αIIbβ3 surface expression. The Cys575Gly mutation may disrupt the disulphide link with Cys586 to cause the GT phenotype. The molecular pathology of the other missense mutations is not clear. Two nonsense mutations, Trp‐16Stop and Glu715Stop in αIIb, and a 7‐bp deletion (330‐336TCCCCAG) in β3 are predicted to result in truncated proteins. An IVS15(−1)G → A mutation in αIIb induced a cryptic splice site as confirmed by reverse transcription‐polymerase chain reaction (RT‐PCR) analysis. Thirteen polymorphisms were also identified (five in αIIb and eight in β3), among which five were novel. Conclusions: While identifying a significant number of novel mutations causing GT, this study confirms the genetic heterogeneity of the disorder in southern India.