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Homozygous Cys 542 →Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia
Author(s) -
Ruan Jian,
Schmugge Markus,
Clemetson Kenneth J.,
Cazes Eric,
Combrie Robert,
Bourre François,
Nurden Alan T.
Publication year - 1999
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.1999.01376.x
Subject(s) - glanzmann's thrombasthenia , thrombasthenia , microbiology and biotechnology , platelet membrane glycoprotein , platelet , chemistry , antibody , point mutation , exon , platelet glycoprotein gpiib iiia complex , complementary dna , biochemistry , mutation , biology , glycoprotein , gene , genetics , integrin , immunology , receptor , platelet aggregation
Glanzmann's thrombasthenia (GT) arises from a qualitative or quantitative defect in the GPIIb–IIIa complex (integrin α IIb β 3 ), the mediator of platelet aggregation. We describe a patient in whom clinical and laboratory findings typical of type I GT were found together with a second pathology involving neurological and other complications symptomatic of tuberous sclerosis. Analysis of platelet proteins by Western blotting revealed trace amounts of normally migrating GPIIb and equally small amounts of GPIIIa of slightly slower than normal migration. Flow cytometry confirmed a much decreased binding to platelets of monoclonal antibodies to GPIIb, GPIIIa or GPIIb–IIIa, and an antibody to the α v subunit also showed decreased binding. Nonradioactive PCR single‐strand conformation polymorphism analysis followed by direct sequencing of PCR‐amplified DNA fragments showed a homozygous point mutation (T to C) at nucleotide 1722 of GPIIIa cDNA and which led to a Cys 542 →Arg substitution in the GPIIIa protein. The mutation gave rise to a HinP1 I restriction site in exon 11 of the GPIIIa gene and allele‐specific restriction enzyme analysis of family members confirmed that a single mutated allele was inherited from each parent. This amino acid substitution presumably changes the capacity for disulphide bond formation within the cysteine‐rich core region of GPIIIa and its study will provide new information on GPIIb–IIIa and α v β 3 structure and biosynthesis.