STUDIES OF HUMAN PIGMENTATION DISORDERS

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DESCRIPTION (Adapted from the Investigator's Abstract): Because of their readily apparent clinical phenotypes, disorders of pigmentation were among the first genetic diseases recognized in humans. The most severe of these are the oculocutaneous albinism (OCA) syndromes, characterized by greatly reduced pigmentation of the skin and eyes, major developmental defects of the visual pathways and consequent low visual acuity, susceptibility to skin cancer, and various other problems. A specific group of OCA disorders is even more severe, with pleiotropic systemic manifestations that lead to premature death. In these "multi-organellar" forms of OCA, which include Hermansky-Pudlak syndrome (HPS) and Chediak-Syndrome (CHS), deficient pigmentation results from defective biogenesis of multiple cellular organelles, including the melanosome, the site of pigment biosynthesis. We have previously identified the genes for HPS and CHS. Here, we propose to continue and extend our studies of HPS and CHS, with particular emphasis on studying the functions of the HPS and CHS proteins in organellar biogenesis and identifying three novel mouse genes, light-ear, cocoa, and buff, which cause HPS-like disorders of the mouse and we believe may likewise cause HPS-like diseases in man. The significance of these studies will be to elucidate the biological basis of these disorders, providing important basic knowledge about organellar biogenesis, but more importantly providing knowledge that may lead to the development of specific and effective therapies to prevent the premature deaths of patients with HPS and CHS.