GENETIC STUDIES OF HUMAN PIGMENTATION DISORDERS

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We have previously defined the molecular basis of two quite different human genetic disorders of pigmentation; type I (tyrosinase-deficient) oculocutaneous albinism (OCA) and piebaldism. Type I OCA is a clinically severe autosomal recessive disorder in which globally defective biosythesis of melanin in pigment cells results from deficient activity of melanocyte tyrosinase. In contrast, piebaldism is an autosomal dominant disorder in which extensive non-pigmented regions of the skin, due to defective proliferation or migration of melanocytes during embryogenesis, result from defects of the cellular receptor for mast/stem cell growth factor. We plan to continue our studies of these two disorders. We will study the molecular basis of type I OCA in several different ethnic groups, including at least Caucasians, Blacks, and Arabs, and apply these findings to improved carrier detection and prenatal diagnosis for this disorder. The effects of specific tyrosinase gene missense substitutions on the multiple catalytic and copper-binding activities of tyrosinase will also be studied, leading to detailed molecular knowledge of this enzyme. We will also continue our studies of the molecular basis of piebaldism, identifying additional mutations of the c-kit proto-oncogene in patients with this disorder. Correlation of c-kit gene mutations with the associated phenotype may identify functionally important sites in the corresponding tyrosine kinase growth factor receptor. We also plan to initiate a long-term project to define the molecular basis of a third clinically important disorder of pigmentation, Waardenburg syndrome, type I, a developmental disorder phenotypically similar to piebaldism, but which affects a somewhat wider array of neural crest-derived cell lineages, resulting in white spotting, deafness, and facial dysmorphia.