MUTATION IN AND LACK OF EXPRESSION OF TYROSINASE-RELATED PROTEIN-1 (TRP-1) IN MELANOCYTES FROM AN INDIVIDUAL WITH BROWN OCULOCUTANEOUS ALBINISM - A NEW SUBTYPE OF ALBINISM CLASSIFIED AS OCA3

Most types of human oculocutaneous albinism (OCA) result from mutation s in the gene for tyrosinase (OCA1) or the P protein (OCA2), although other types of OCA have been described but have not been mapped to spe cific loci, Melanocytes were cultured from an African-American with OC A, who exhibited the phenotype of Brown OCA, and his normal fraternal twin. Melanocytes cultured from the patient with OCA and the normal tw in appeared brown versus black, respectively. Melanocytes from both th e patient with OCA and the normal twin demonstrated equal amounts of N P-40-soluble melanin; however, melanocytes from the patient with OCA c ontained only 7% of the amount of insoluble melanin found from the nor mal twin. Tyrosinase-related protein-1 (TRP-1) was not detected in the OCA melanocytes by use of various anti-TRP-l probes. Furthermore, tra nscripts for TRP-1 were absent in cultured OCA melanocytes. The affect ed twin was homozygous for a single-bp deletion in exon 6, removing an A in codon 368 and leading to a premature stop at codon 384. Tyrosine hydroxylase activity of the OCA melanocytes was comparable to control s when assayed in cell lysates but was only 30% of controls when assay ed in intact cells. We conclude that this mutation of the human TRP-1 gene affects its interaction with tyrosinase, resulting in dysregulati on of tyrosinase activity, promotes the synthesis of brown versus blac k melanin, and is responsible for a third genetic type of OCA in human s, which we classify as ''OCA3.''