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A novel (288delC) mutation in exon 2 of GPIIb associated with type I Glanzmann's thrombasthenia
Author(s) -
Tao Jianming,
AriasSalgado Elena García,
GonzálezManchón Consuelo,
DíazCremades Juan,
Ayuso Matilde S.,
Parrilla Roberto
Publication year - 2000
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.1365-2141.2000.02336.x
Subject(s) - glanzmann's thrombasthenia , thrombasthenia , exon , microbiology and biotechnology , nonsense mutation , platelet , chinese hamster ovary cell , mutation , chemistry , biology , biochemistry , immunology , gene , missense mutation , receptor , platelet aggregation
This work reports the molecular genetic analysis of two patients who suffer mucocutaneous haemorrhages, prolonged bleeding time and failure of platelets to aggregate, either spontaneously or in response to agonists. The absence of platelet surface glycoprotein (GP)IIb–IIIa complexes confirmed the clinical diagnosis of Glanzmann's thrombasthenia (GT). Polymerase chain reaction single‐strand conformation polymorphism (PCR‐SSCP) analysis of exon 2 of GPIIb showed polymorphic bands caused by the homozygous deletion of a cytosine at position 288 relative to the translation start site, causing a shifting of the reading frame and appearance of a premature termination codon. The heterozygous relatives showed a reduced platelet content of GPIIb–IIIa, and a correlation was found between the levels of GPIIb mRNA and surface expression of GPIIb–IIIa complexes. Unlike other mRNAs carrying a nonsense mutation, (288Cdel)GPIIb does not force alternative splicing of GPIIb mRNA. As expected, co‐transfection of Chinese hamster ovary (CHO) cells with cDNAs encoding GPIIIa and (288delC)GPIIb failed to enhance the surface exposure of GPIIIa. It is concluded that the (288delC)GPIIb mutation is responsible for the thrombasthenic phenotype of the patients. In addition, it has also been determined that heterodimerization of GPIIb–IIIa requires the integrity of exons 2 and 3 of GPIIb.