Triple heterozygosity in the integrin alphaIIb subunit in a patient with Glanzmann's thrombasthenia.
J Thromb Haemost
; 2(5): 813-9, 2004 May.
Article
en En
| MEDLINE
| ID: mdl-15099289
ABSTRACT
We report triple heterozygosity in the integrin alpha(IIb) subunit in a 5-year-old Canadian girl with Glanzmann's thrombasthenia. The patient has a severe bleeding history possibly aggravated by low VWF suggestive of associated type 1 von Willebrand's disease. Platelet aggregation was absent or severely reduced for all physiologic agonists. Flow cytometry showed an approximately 4% residual surface expression of alpha(IIb)beta(3). Western blotting confirmed a low platelet expression of both subunits. PCR-SSCP and direct sequencing showed no abnormalities in the beta(3) gene, but revealed a G-->A transition at a splice site [IVS 19 (+1)] of exon 19 in the alpha(IIb) gene. Of maternal inheritance, the splice site mutation was associated with intermediate levels of alpha(IIb)beta(3) in carriers. Unexpectedly, two G-->A transitions were detected in exon 29 of the alpha(IIb) gene and led to V(951)-->M and A(958)-->T amino acid substitutions. Family studies using restriction enzymes showed that both exon 29 mutations were paternal in origin and cosegregated across three generations. Transient expression in which mutated alpha(IIb) was cotransfected with wild-type beta(3) in COS-7 cells showed that V(951)-->M gave a much reduced surface expression of alpha(IIb)beta(3) and a block in the maturation of pro-alpha(IIb). In contrast, the A(958) substitution appeared to be a novel polymorphism. Our studies highlight an unusual mixture of defects giving rise to severe bleeding in a child and describe the first pathological missense mutation affecting a C-terminal residue of the calf-2 domain of alpha(IIb).
Buscar en Google
Base de datos:
MEDLINE
Asunto principal:
Trombastenia
/
Mutación Puntual
/
Glicoproteína IIb de Membrana Plaquetaria
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2004
Tipo del documento:
Article