MOLECULAR BASIS OF THE CHEDIAK-HIGASHI SYNDROME

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Oculocutaneous albinism represents a heterogeneous group of genetic disorders characterized by reduced to absent production of melanin pigment in association with specific changes in the developing eye. In addition to primary abnormalities in melanin synthesis, reduced pigmentation may be a component of a multisystemic process. The Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by partial oculocutaneous albinism, immunodeficiency, and a marked predisposition to lymphoproliferative disease. The gene responsible for the well- characterized mouse model of CHS, beige (bg), was recently isolated by positional cloning, providing the first opportunity for understanding this disorder at a molecular level. The molecular basis of this cause of oculocutaneous albinism will be investigated here by a genetic complementation approach involving the retrovirus-mediated expression of antisense RNA to bg coding and 3 - untranslated sequences in normal mouse melanocytes and of a full-length sense cDNA in beige mouse melanocytes and CHS patient-derived fibroblast and lymphoblast cell lines. These studies will provide functional confirmation that the CHS gene has been identified, complement efforts at identifying mutations in the human ortholog of the bg gene and in other bg alleles, determine whether more than one complementation group exists in this disorder, and generate valuable reagents for investigating the function of this gene in melanosomal biogenesis.