SearchPublisher and Institutes
You are here: Home :: Area NEM :: Medical science :: Human medicine
Jingli Xie, Dina Pabn, Asier Jayo, Nora Butta, Consuelo Gonzlez-Manchn
Type I Glanzmann thrombasthenia caused by an apparently silent 3 mutation that results in aberrant splicing and reduced 3 mRNA
We report a novel genetic defect in a patient with type I Glanzmann thrombasthenia. Flow cytometry analysis revealed undetectable levels of platelet glycoproteins IIb and 3, although residual amounts of both proteins were detectable in immunoblotting analysis. Sequence analysis of reversely transcribed platelet 3 mRNA showed a 100-base pair deletion in the 3-boundary of exon 11, that results in a frame shift and appearance of a premature STOP codon. Analysis of the corresponding genomic DNA fragment revealed the presence of a homozygous C1815T transition in exon 11. The mutation does not change the amino acid residue but it creates an ectopic consensus splice donor site that is used preferentially, causing splicing out of part of exon 11. The parents of the proband, heterozygous for this mutation, were asymptomatic and had reduced platelet content of IIb3. PCR-based relative quantification of 3 mRNA failed to detect the mutant transcript in the parents and showed a marked reduction in the patient. The results suggest that the thrombasthenic phenotype is, mainly, the result of the reduced availability of 3-mRNA, most probably due to activation of the nonsense-mediated mRNA decay mechanism. They also show the convenience of analyzing both genomic DNA and mRNA, in order to ascertain the functional consequences of single nucleotide substitutions.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 93, 05/2005
Pages: 897 - 903