Albinism in Africa and human pigmentation genetics
Principal Investigator: Prof Michele Ramsay
Collaborators: Prof J Kromberg (Johannesburg - more recently Brisbane), Prof R Nicholls (Philadelphia), Dr R Sturm (Brisbane) and Dr W-H Li (Chicago), Dr S Kidson (Cape Town), Sr E Zwane (Johannesburg)
-- The main objective of this project is to improve our understanding of the different steps involved in the pigmentary pathway through the study of naturally occurring human pigment disorders. Oculocutaneous albinism (OCA) is a common genetic disorder in Africa with major health implications in terms of increased susceptibility to early onset skin cancer and the need for special education in schools for the partially sighted. In South African blacks the prevalence of OCA is 1 in 3900.
Over the past 10 years we have made significant progress towards understanding the molecular basis of oculocutaneous albinism 2 (OCA2 - MIM2032000). In 1992 the locus was mapped to chromosome 15q11.2-q12 and when the P was identified in the region it was shown that this was the locus involved in the South African OCA2 individuals. A common P gene mutation has been identified and is present in 77% of South African blacks (giving a frequency of 0.77). This mutation is a 2.7kb interstitial deletion which deleted exon 7, and which results in a downstream frameshift. In an effort to accurately predict the carrier frequency, 780 healthy unaffected individuals were studied and the carrier frequency of the 2.7kb deletion was shown to be 1 in 78 in South African black OCA2 individuals. If one corrects for a detection rate of 0.77, them the OCA2 carrier frequency is about 1 in 40. We screened the coding region of the P gene for mutations in the non-2.7kb deletion alleles of OCA2 patients who did not carry the deletion allele in either one or both of their P genes. We identified four mutations (A334V, 614delA, 683insT, 727insG) in a group of 39 unrelated black OCA2 patients with a total of 52 non-2.7kb deletion OCA2 genes. When taking all OCA2 cases into consideration, including those homozygous for the 2.7kb deletion mutation, these account for a further 1.7% of OCA2 mutations in southern African blacks, increasing the overall mutation detection rate to 78.7%. Three mutations (E678K, L688F, I370T) were identified in a group of 15 black patients with an initially unclassified type of OCA and another three mutations (IVS14-2(a*g), V350M, P743L) were identified in nine caucasoid OCA patients. Relatively few mutations, all with low frequency, were identified in the non-2.7kb deletion OCA genes suggesting that other mutations may lie either within intronic sequence, or within the promoter region of the gene.
Two other types of oculocutaneous albinism have been shown to be relatively common in southern African blacks, namely brown and rufous OCA. Brown OCA (BOCA - MIM 203290) has been shown to be allelic to OCA2 in South African blacks, with the majority of affected individuals being compound heterozygotes, with one 2.7kb deletion allele. Rufous OCA (ROCA - MIM 278400) has been shown to be caused by mutations in the tyrosinase-related protein 1 locus on chromosome 9p23. Two mutations, S166X and 368delA account for 0.95 of mutations in 19 unrelated affected individuals.
Current projects are aimed at identifying the promoter region of the P gene in order to search for OCA2 and BOCA mutations and at understanding the molecular basis of ephelides (pigmented patches) (see photograph) that occur in a large proportion of OCA2 affected individuals.
Preliminary studies on understanding the molecular basis of normal pigmentation differences in humans included exploring the role of the MC1R gene in normal pigment variation. The MC1R gene was studied in negroid and San populations and also in a group of individuals with red hair. The two African groups had fewer non-synonymous than synonymous substitutions. All red-haired individuals of European origin were either homozygotes or compound heterozygotes for MC1R mutations. Four novel mutations were detected in these individuals: S83P, Y152X, A171N and P256S.
