RUFOUS OCULOCUTANEOUS ALBINISM IN SOUTHERN AFRICAN BLACKS IS CAUSED BY MUTATIONS IN THE TYRP1 GENE

Oculocutaneous albinism (OCA) is the most common autosomal recessive d isorder among southern African Blacks. There are three forms that acco unt for almost all OCA types in this region. Tyrosinase-positive OCA ( OCA2), which is the most common, affects similar to 1/3,900 newborns a nd has a carrier frequency of similar to 1/33. It is caused by mutatio ns in the P gene on chromosome 15. Brown OCA (BOCA) and rufous OCA (RO CA) account for the majority of the remaining phenotypes. The prevalen ce of BOCA is unknown, but for ROCA it is similar to 1/8,500. Linkage analysis performed on nine ROCA families showed that ROCA was linked t o an intragenic marker at the TYRP1 locus (maximum LOD score = 3.80 at theta = .00). Mutation analysis of 19 unrelated ROCA individuals reve aled;a nonsense mutation at codon 166 (S166X) in 17 (45%) of 38 ROCA c hromosomes, and a-second mutation (368delA) was found in an additional 19 (50%) of 38 chromosomes; mutations were not identified in the rema ining 2 ROCA chromosomes. In one family, two siblings with a phenotypi cally unclassified form of albinism were found to be compound heterozy gotes for mutations (S166X/368delA) at the TYRP1 locus and were hetero zygous for a common 2.7-kb deletion in the P gene. These findings have highlighted the influence of genetic background on phenotype, in whic h the genotype at one locus can be influenced by the genotype at a sec ond locus, leading to a modified phenotype. ROCA, which in southern Af rican Blacks is caused by mutations in the TYRP1 gene, therefore shoul d be referred to as ''OCA3,'' since this is the third locus that has b een shown to cause an OCA phenotype in humans.