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Título : A novel homozygous splice junction mutation in GPIIb associated with alternative splicing, nonsense-mediated decay of GPIIb-mRNA, and type II Glanzmann's thrombasthenia
Autor : González-Manchón, Consuelo ; García Arias-Salgado, Elena ; Butta, Nora ; Martín, G.; Rodríguez, Ramón B.; Elalamy, Ismaïl; Parrilla, Roberto L. ; Favier, Rémi
Palabras clave : Glanzmann's thrombasthenia
GPIIb
mRNA decay
Splicing
Fecha de publicación : 25-abr-2003
Editor: Blackwell Publishing
International Society on Thrombosis and Haemostasis
Citación : Journal of Thrombosis and Haemostasis (5):1071-1078(2003)
Resumen: This work reports the study of a patient suffering a bleeding disorder clinically diagnosed as Glanzmann's thrombasthenia (GT). Immunoblotting and flow cytometric analysis showed a low (≤ 10% of control) platelet content of GPIIb–IIIa, confirming it was indeed a type II GT. The molecular genetic analysis of the proband revealed the presence of a homozygous G188A transition in GPIIb. This mutation alters the consensus sequence of the splice donor site of intron 1 changing arginine 63 for lysine (R63K). No other mutation than [G188A]GPIIb was found in the proband and her parents after complete analysis of GPIIb and GPIIIa coding sequences, and the promoter, 3'-UTR, and intronic flanking regions of GPIIb. The GT phenotype of the proband is the result of a limited availability of GPIIb-mRNA. The etiopathogenic role of the [G188A]GPIIb mutation is supported by the following observations: (i) both parents, who are heterozygous for the [G188A]GPIIb mutation, show a marked decrease in the platelet content of GPIIb-mRNA; (ii) exontrap analysis demonstrated that the G188A mutation leads to a marked reduction in the steady-state level of GPIIb-mRNA. The reduced availability of platelet GPIIb-mRNA associated with the G188A mutation seems to be caused by either inefficient RNA splicing or a preferred utilization of alternative intronic donor sites that generate an in-frame STOP codon with the result of activation of nonsense-mediated mRNA decay, or both.
Descripción : 8 pages.
Versión del editor: http://dx.doi.org/10.1046/j.1538-7836.2003.00204.x
URI : http://hdl.handle.net/10261/6336
DOI: 10.1046/j.1538-7836.2003.00204.x
ISSN: 1538-7836
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