Genes in the Aetiology of Oculocutaneous Albinism in Sub-Saharan Africa and a Possible Role in Tuberculosis Susceptibility
Year: 2008
Type: dissertation
Study design: Observational Study
Abstract: ABSTRACT \nIn southern Africa, oculocutaneous albinism (OCA) is the most common autosomal \nrecessive disease amongst black Africans, occurring with a prevalence of approximately 1 \nin 3 900 individuals. OCA occurs in southern African Caucasoids with a frequency that \nreflects the European origins of this population, approximately 1 in 20-30 000. OCA type 1 \nis caused by mutations in the tyrosinase gene on chromosome 11q. Tyrosinase mutations \noccur in the Caucasoid population but are extremely rare in black Africans. OCA type 2 is \ncaused by mutations in the P gene on chromosome 15q. P gene mutations occur in both the \nblack and Caucasoid populations. A sub-type of OCA2 seen in black individuals, brown \nOCA (BOCA), is also caused by mutations at the P gene locus. \nA mutation screen was undertaken to identify disease-causing mutations in a group of OCA \nsubjects from Sub-Saharan Africa. A common P gene mutation had been identified in the \nblack population, a 2.7 kb intragenic deletion, accounting for 78% of P gene mutations in \nthis group. No common tyrosinase mutations have been identified to date, in any \npopulation. A cohort of OCA subjects from South Africa, Lesotho, Zambia and the Central \nAfrican Republic (CAR) were available for study in our laboratory. All subjects were \nscreened for the 2.7 kb deletion mutation. Subjects homozygous for this mutation were \nexcluded from further study. Subjects where one or two mutations remained to be \nidentified were included in a mutation screen (63 blacks and 9 Caucasoids). Depending on \nthe clinical categorisation of the type of albinism, subjects were screened for P gene \nmutations only (black OCA2) or were screened for P gene mutations and tyrosinase \nmutations (BOCA, unclassified black OCA and unclassified Caucasoid OCA). \nAll 72 subjects were screened for P gene mutations and ten putative pathogenic mutations \nwere identified. In the group of black OCA2 patients, four mutations which are likely to be \npathogenic were found: A334V, 614delA, 683insT and 727insG. Mutations were identified \nin four individuals with an unusual hypopigmentation phenotype: E678K was found in the \nhomozygous state in an individual from the CAR. A second individual was found to be a \ncompound heterozygote for the I370T and the L688F mutations. A third individual was \nfound to be heterozygous for the I370T mutation. Three P gene mutations were found in the Caucasoid sample: IVS 14-2 (a→g), V350M and P743L. No further mutations were \nidentified in the BOCA sample. The P gene screen comprised 72 subjects, but 40 were \nheterozygous for the 2.7 kb deletion, therefore (144 minus 40 alleles) 104 alleles remained \nto be identified. Identification of 12/104 alleles means that a further 11.5% of the unknown \nP gene mutations are now accounted for. Thirty three of the 72 subjects were included in a \nfurther mutation screen – at the tyrosinase locus. Four mutations were identified, all in the \nCaucasoid group. Compound heterozygosity was shown in two individuals, one carrying \nthe mutations, E294K and A490D and the other, P431T and T373K. \nFollowing mutation analysis of the P gene, it was apparent that a proportion of mutations \ndid not lie in the coding region of the gene and it was proposed that some of the remaning \nunidentified mutations might be found in the 5’control or promoter region of the gene. At \nthat time, sequence data for the region upstream of the P gene was not known, and so an \nattempt was made to clone the 5’region of the P gene. Two approaches were adopted – a \nbacterial artificial chromosome (BAC) known to contain this region was subcloned; and \nsecondly, an inverse PCR experiment was undertaken. Neither experiment was successful \nin generating P gene promoter sequence. \nVariation at the P locus was investigated in a second context. This region of chromosome \n15q was implicated as a host susceptibility locus for the infectious disease, tuberculosis \n(TB). A case-control study was undertaken to compare the frequencies of five intragenic, \npolymorphic markers in the P gene: the 2.7 kb deletion, the R305W polymorphism and the \nmicrosatellite markers, D15S1533, D15S1536 and D15S1537, between a group of black \nSouth African TB patients from Gauteng and healthy community controls and between a \ngroup of mixed-ancestry (Coloured) TB patients and healthy controls from the Western \nCape region. Presence or absence of the 2.7 kb deletion mutation does not appear to \ninfluence susceptibility to TB in either the black or Coloured population samples studied \nhere. The W allele of the R305W polymorphism is significantly (p<0.05) more common in \nthe black patient group than in the black control group, suggesting it may be in linkage \ndisequilibrium with a disease susceptibility allele. Microsatellite marker analysis showed \nthat, in the black population, allele 18 at the D15S1533 locus is significantly (p<0.05) \nassociated with susceptibility to TB. In the Cape Coloured population, alleles 20 and 27 at \nthe D15S1533 locus, allele 12 at the D15S1536 locus and allele 16 at the D15S1537 locus \nare over represented in the patient group suggesting they may be markers for increased susceptibility to TB. Further, in the Coloured population alleles 12, 13 and 15 at the \nD15S1537 locus showed significant (p<0.05) association with normal controls and may be \nin linkage disequilibrium with protective or resistance alleles. \nThe results of this study support the proposal of a TB susceptibility locus on chromosome \n15q. OCA-causing mutations have been identified, but many remain elusive. Further \ncharacterisation of this region will give us a better understanding of the biological \nconsequences of variation both within and around the P locus.
Author: Robyn Kerr
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2116652106