HUMAN BIOCHEMICAL GENETICS

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Members of the Section, having mapped the cystinosis gene to chromosome 17p, have now narrowed the region of the gene to a 130 kb span by identifying new polymorphic markers and informative recombinants. Several nonpolymorphic markers have been mapped to the area by radiation hybrid analysis. Two P1 clones span the cystinosis gene region, flanked by markers D17S1828 and D17S2167. Since they overlap, the cystinosis gene must be located on one of the clones. The identification and testing of candidate genes continues. We have identified 24 rab proteins (small, monomeric GTP-binding proteins) in melanocytes. Rab30 represents a novel protein of 203 amino acids, and rab22b appears to be an isoform of the human homologue of canine rab22. Furthermore, rab27a and rab27b, which comprise a rab subfamily expressed in both melanocytes and platelets, are candidates for involvement in human and mouse disorders of pigment dilution and a platelet storage pool defect. A tyrosine transport system has been characterized in the melanosomes of murine melanocytes. It exhibits countertransport and saturability, with an apparent Km for tyrosine of 54 microM. In its substrate preferences, it resembles lysosomal system h of rat thyroid FRTL-5 cells. The melanocyte's melanosomal transport system appears critical for the production of the pigment melanin. The Section has examined over 30 patients with Hermansky-Pudlak syndrome, a disorder consisting of albinism, a bleeding diathesis, and lysosomal storage of ceroid lipofuscin. Half the patients have been Puerto Rican. Dolichols have been identified as components of the ceroid lipofuscin and several patients have exhibited increased levels of cholesterol and coenzyme Q10, all suggesting involvemnt of the cholesterol synthetic pathway in this disorder. Clinical characterization of the disease may point to avenues of therapy.