THE TYROSINASE-POSITIVE OCULOCUTANEOUS ALBINISM GENE SHOWS LOCUS HOMOGENEITY ON CHROMOSOME 15Q11-Q13 AND EVIDENCE OF MULTIPLE MUTATIONS IN SOUTHERN AFRICAN NEGROIDS

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is an autosom al recessive disorder of the melanin pigmentary system. South African ty-pos OCA individuals occur with two distinct phenotypes, with or wit hout darkly pigmented patches (ephelides, or dendritic freckles) on ex posed areas of the skin. These phenotypes are concordant within famili es, suggesting that there may be more than one mutation at the ty-pos OCA locus. Linkage studies carried out in 41 families have shown linka ge between markers in the Prader-Willi/Angelman syndrome (PWS/AS) regi on on chromosome 15q11-q13 and ty-pos OCA. Analysis showed no obligato ry crossovers between the alleles at the D15S12 locus and ty-pos OCA, suggesting that the D15S12 locus is very close to or part of the disea se locus, which is postulated to be the human homologue, P, of the mou se pink-eyed dilution gene, p. Unlike caucasoid ''ty-pos OCA'' individ uals, negroid ty-pos OCA individuals do not show any evidence of locus heterogeneity. Studies of allelic association between the polymorphic alleles detected at the D15S12 locus and ephelus status suggest that there was a single major mutation giving rise to ty-pos OCA without ep helides. There may, however, be two major mutations causing ty-pos OCA with ephelides, one associated with D15S12 allele 1 and the other ass ociated with D15S12 allele 2. The two loci, GABRA5 and D15S24, flankin g D15S12, are both hypervariable, and many different haplotypes were o bserved with the alleles at the three loci on both ty-pos OCA-associat ed chromosomes and ''normal'' chromosomes. No haplotype showed statist ically significant association with ty-pos OCA, and thus none could be used to predict the origins of the ty-pos OCA mutations. On the basis of the D15S12 results, there is evidence for multiple ty-pos OCA muta tions in southern African negroids.