5 '-UTR structural organization, transcript expression, and mutational analysis of the human Rab geranylgeranyl transferase alpha-subunit (RABGGTA) gene

Hermansky-Pudlak syndrome (HPS) is a recessively inherited disease with dys function of several related subcellular organelles including platelet-dense granules, melanosomes, and lysosomes, Our recent identification of the mut ation in murine Rab geranylgeranyl transferase alpha -subunit gene (Rabggta ) in one mouse model of HPS, the gunmetal mouse, suggested that human patie nts with similar phenotypes might have mutations in the human orthologous R ABGGTA gene. This prompted reanalysis of the 5'-untranslated structure of t he human RABGGTA gene in normal individuals and in patients with deficienci es of platelet-dense granules (alpha delta -SPD), alpha granules (alpha -SP D or gray platelet syndrome, GPS) or alpha plus dense granules (alpha delta -SPD), We report the complete sequence of intron alpha of RABGGTA and demo nstrate that exon alpha is immediately upstream of intron alpha. The exon/i ntron structural organization of the 5'-untranslated region (UTR) of human RABGGTA was found to be similar to that of the mouse Rabggta gene. However, exons alpha and introns alpha are not homologous between mouse and human. Features of the 5'-UTR of RABGGTA suggest it is a housekeeping gene. While obvious disease-causing mutations of human RABGGTA were not found in our ex isting SPD patients by sequencing its entire coding region, several polymor phisms of RABGGTA including a putative cryptic splicing mutation in intron 4 were identified. Knowledge of the 5'-UTR structure of RABGGTA and its com mon polymorphisms will be useful for mutation screening or linkage analysis in patients with albinism, thrombocytopenia, or platelet SPD. (C) 2000 Aca demic Press.