Diversity of Glanzmann thrombasthenia in southern India: 10 novel mutations identified among 15 unrelated patients.
J Thromb Haemost
; 4(8): 1730-7, 2006 Aug.
Article
em En
| MEDLINE
| ID: mdl-16879215
ABSTRACT
BACKGROUND:
Glanzmann thrombasthenia (GT) is a congenital bleeding disorder caused by either a lack or dysfunction of the platelet integrin alphaIIbbeta3.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 alphaIIbbeta3 was < 10%, 10%-50%, and > 50% of controls in five, nine, and one patient(s), respectively. Immunoblotting of the platelet lysates showed no alphaIIb in 14 patients, and no beta3 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 alphaIIbbeta3 expression, and normal alphaIIb, beta3 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 alphaIIb, and Cys575Gly in beta3. We have already shown that Gly128Ser, Ser287Leu, and Gly357Ser mutations variably affect alphaIIbbeta3 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 alphaIIb, and a 7-bp deletion (330-336TCCCCAG) in beta3 are predicted to result in truncated proteins. An IVS15(-1)G --> A mutation in alphaIIb induced a cryptic splice site as confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Thirteen polymorphisms were also identified (five in alphaIIb and eight in beta3), 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.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Polimorfismo Genético
/
Plaquetas
/
Trombastenia
/
Complexo Glicoproteico GPIIb-IIIa de Plaquetas
/
Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Child
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Thromb Haemost
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Índia