Combined deficiency of RAB32 and RAB38 in the mouse mimics Hermansky-Pudlak syndrome and critically impairs thrombosis.
Fiche publication
Date publication
août 2019
Journal
Blood advances
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GACHET Christian
Tous les auteurs :
Aguilar A, Weber J, Boscher J, Freund M, Ziessel C, Eckly A, Magnenat S, Bourdon C, Hechler B, Mangin PH, Gachet C, Lanza F, Léon C
Lien Pubmed
Résumé
The biogenesis of lysosome related organelles is defective in Hermansky-Pudlak syndrome (HPS), a disorder characterized by oculocutaneous albinism and platelet dense granule (DG) defects. The first animal model of HPS was the fawn-hooded rat, harboring a spontaneous mutation inactivating the small guanosine triphosphatase This leads to coat color dilution associated with the absence of DGs and lung morphological defects. Another RAB38 mutant, the mouse, has normal DGs, which has raised controversy about the role of RAB38 in DG biogenesis. We show here that murine and human, but not rat, platelets also express the closely related RAB32. To elucidate the parts played by RAB32 and RAB38 in the biogenesis of DGs in vivo and their effects on platelet functions, we generated mice inactivated for , and both genes. Single inactivation mimicked mice, whereas single inactivation had no effect in DGs, coat color, or lung morphology. By contrast, double inactivation mimicked severe HPS, with strong coat and eye pigment dilution, some enlarged lung multilamellar bodies associated with a decrease in the number of DGs. These organelles were morphologically abnormal, decreased in number, and devoid of 5-hydroxytryptamine content. In line with the storage pool defect, platelet activation was affected, resulting in severely impaired thrombus growth and prolongation of the bleeding time. Overall, our study demonstrates the absence of impact of RAB38 or RAB32 single deficiency in platelet biogenesis and function resulting from full redundancy, and characterized a new mouse model mimicking HPS devoid of DG content.
Référence
Blood Adv. 2019 Aug 13;3(15):2368-2380