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Thromb Haemost 2005; 93(05): 897-903
DOI: 10.1160/TH04-09-0633
Platelets and Blood Cells
Schattauer GmbH

Type I Glanzmann thrombasthenia caused by an apparently silent β3 mutation that results in aberrant splicing and reduced β3 mRNA

Jingli Xie
1   Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
,
Dina Pabón
1   Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
,
Asier Jayo
1   Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
,
Nora Butta
1   Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
,
Consuelo González-Manchón
1   Department of Pathophysiology and Human Molecular Genetics, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain
› Author AffiliationsFinancial support: Supported in part by grants from the Direccion General de Investigacion (SAF 2000–0127 and BMC2003–01409), and Fondo de Investigaciones Sanitarias (FIS-PI021263). N. Butta is recipient of a tenure track grant Ramon y Cajal from the Spanish Ministry of Science. J. Xie and A. Jayo are recipients of fellowships from the Agencia Es-pañola de Cooperación Internacional (AECI, Ref. 2002CN0004) and Ministerio de Educación y Ciencia, respectively.
Further Information

Publication History

Received 28 September 2004

Accepted after resubmission 21 January 2005

Publication Date:
11 December 2017 (online)

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Summary

We report a novel genetic defect in a patient with type I Glanzmann thrombasthenia. Flow cytometry analysis revealed undetectable levels of platelet glycoproteins αIIb and β3, although residual amounts of both proteins were detectable in immunoblotting analysis. Sequence analysis of reversely transcribed platelet β3 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 αIIbβ3. PCR-based relative quantification of β3 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 β3-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.

Keywords

Platelets - αIIbβ3 - thrombasthenia - splicing mutation
 

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