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Triple heterozygosity in the integrin α IIb subunit in a patient with Glanzmann's thrombasthenia
Author(s) -
Nurden A. T.,
Breillat C.,
Jacquelin B.,
Combrié R.,
Freedman J.,
Blanchette V. S.,
Schmugge M.,
Rand M. L.
Publication year - 2004
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1046/j.1538-7836.2004.00711.x
Subject(s) - exon , loss of heterozygosity , glanzmann's thrombasthenia , missense mutation , compound heterozygosity , microbiology and biotechnology , biology , thrombasthenia , splice site mutation , splice , genetics , mutation , alternative splicing , platelet , gene , allele , immunology , platelet aggregation
Summary. We report triple heterozygosity in the integrin α 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 ∼ 4% residual surface expression of α IIb β 3 . Western blotting confirmed a low platelet expression of both subunits. PCR‐SSCP and direct sequencing showed no abnormalities in the β 3 gene, but revealed a G→A transition at a splice site [IVS 19 (+1)] of exon 19 in the α IIb gene. Of maternal inheritance, the splice site mutation was associated with intermediate levels of α IIb β 3 in carriers. Unexpectedly, two G→A transitions were detected in exon 29 of the α 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 α IIb was cotransfected with wild‐type β 3 in COS‐7 cells showed that V 951 →M gave a much reduced surface expression of α IIb β 3 and a block in the maturation of pro‐α 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 α IIb .