期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 3, 期 12, 页码 2773-2783出版社
WILEY
DOI: 10.1111/j.1538-7836.2005.01593.x
关键词
alpha(IIb)beta(3) biogenesis; beta-propeller mutations; Glanzmann thrombasthenia
资金
- NCRR NIH HHS [M01 RR000102, M01-RR00102] Funding Source: Medline
- NHLBI NIH HHS [R01 HL019278] Funding Source: Medline
Background: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterized by lack of platelet aggregation in response to most physiological agonists and caused by either a lack or dysfunction of the platelet integrin alpha(IIb)beta(3) (glycoprotein IIb/IIIa). Objectives: To determine the molecular basis of GT and characterize the mutations by in vitro expression studies. Patients: We studied three unrelated patients from southern India whose diagnosis was consistent with GT. Results: Immunoprecipitation of the cell lysates and immunoblotting showed no detectable mature alpha(IIb) in the G128S mutant, in contrast to 6% and 33% of the normal amount of mature alpha(IIb) in the S287L and G357S mutants, respectively. Pulse-chase analysis demonstrated pro-alpha(IIb) in the mutants comparable with the normal pro-alpha(IIb), but no conversion to mature alpha(IIb) in the G128S mutant, and only trace conversion to mature alpha(IIb) in the S287L and G357S mutants. The disappearance of pro-alpha(IIb) in the three mutants was similar to that in cells expressing normal alpha(IIb)beta(3) or alpha(IIb) only. All three mutants demonstrated pro-alpha(IIb)beta(3) complexes and co-localized with an ER marker by immunofluorescence. The G128S mutant showed no co-localization with a Golgi marker, and the other two mutants showed minimal and moderate co-localization with the Golgi marker. Conclusions: These three beta-propeller mutations do not affect the production of pro-alpha(IIb), its ability to complex with beta(3), or its stability, but do cause variable defects in transport of pro-alpha(IIb)beta(3) complexes from the endoplasmic reticulum to the Golgi.
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