Three novel beta-propeller mutations causing Glanzmann thrombasthenia result in production of normally stable pro-alphaIIb, but variably impaired progression of pro-alphaIIbbeta3 from endoplasmic reticulum to Golgi.
J Thromb Haemost
; 3(12): 2773-83, 2005 Dec.
Article
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| MEDLINE
| ID: mdl-16359515
ABSTRACT
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)beta3 (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)beta3 or alpha(IIb) only. All three mutants demonstrated pro-alpha(IIb)beta3 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 beta3, or its stability, but do cause variable defects in transport of pro-alpha(IIb)beta3 complexes from the endoplasmic reticulum to the Golgi.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Trombastenia
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Complejo GPIIb-IIIa de Glicoproteína Plaquetaria
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Mutación Missense
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Glicoproteína IIb de Membrana Plaquetaria
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Retículo Endoplásmico
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Aparato de Golgi
Límite:
Adult
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Revista:
J Thromb Haemost
Asunto de la revista:
HEMATOLOGIA
Año:
2005
Tipo del documento:
Article
País de afiliación:
Estados Unidos