| Title | Type I Glanzmann thrombasthenia caused by an apparently silent beta3 mutation that results in aberrant splicing and reduced beta3 mRNA. | | Author(s) | Xie J, Pabón D, Jayo A, Butta N, González-Manchón C | | Institution | Department of Pathophysiology and Human Molecular Genetics Centro de Investigaciones Biológicas (CSIC) Ramiro de Maeztu, Madrid, Spain. | | Source | Thromb Haemost 2005 May; 93(5):897-903. | | MeSH | Alleles
Alternative Splicing
Animals
Antibodies, Monoclonal
Blood Platelets
CHO Cells
Child, Preschool
Codon, Nonsense
Codon, Terminator
Cricetinae
DNA
Exons
Family Health
Fathers
Female
Fibrinogen
Flow Cytometry
Frameshift Mutation
Genetic Techniques
Homozygote
Humans
Immunoprecipitation
Integrin beta3
Male
Mice
Models, Genetic
Mothers
Mutation
Phenotype
Platelet Glycoprotein GPIIb-IIIa Complex
Polymerase Chain Reaction
RNA, Messenger
Research Support, Non-U.S. Gov't
Sequence Analysis, DNA
Thrombasthenia
| | Abstract | We report a novel genetic defect in a patient with type I Glanzmann thrombasthenia. Flow cytometry analysis revealed undetectable levels of platelet glycoproteins alphaIIb and beta3, although residual amounts of both proteins were detectable in immunoblotting analysis. Sequence analysis of reversely transcribed platelet beta3 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 alphaIIbbeta3. PCR-based relative quantification of beta3 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 beta3-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. | | Language | eng | | Pub Type(s) | Case Reports
Journal Article
| | PubMed ID | 15886806 |
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