A Search for Transferase Galactosemia Genes in the South African Negroid Population

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Transferase galactosemia is an autosomal recessively inherited disorder caused by a block in the \nconversion of galactose to glucose. Manifestations include jaundice, vomiting, cataracts, mental \nretardation, speech abnormalities and poor growth. This disorder is due to a deficiency of galactose- \n1-phosphate uridyl transferase (GAIT), an enzyme which catalyses the conversion of \nuridyldisphosphoglucose (UDPG) and galactose-l-phosphate to uridyldisphosphogalactose \n(UDPGal) and glucose-1-phosphate. The GALT gene has been mapped and 50 mutations have \nbeen reported in this; gene to date. \nThe aims of this project were to identity and characterise galactosemia-causing mutations in the \nSouth African negroid population and to determine the frequency of these mutations in order to \nestimate the incidence of transferase galactosemia in the South African negroid population. Twentysix \nnegroid patients and one obligate carrier were investigated and the SI35L mutation was found to \naccount for approximately 91% (48/53) of galactosemia alleles in this group. The estimated S135L \nallele carrier frequency in 600 healthy unrelated negroid individuals (1/75) was used in conjunction \nwith the proportion of non-S135L galactosemia alleles present in galactosemics to arrive at an \nestimated galactosemia incidence of 1 per 18 455 births. This is over three times the estimated world \naverage of one per 70 000. \nThree caucasoid galactosemia patients, one galactosemic patient of mixed ancestry and two obligate \ncarriers (one caucasoid and one of mixed ancestry) were screened for mutations in the GALT gene. \nThe Q188R mutation was found to account for 57% (4/7) of the galactosemia mutations in the South \nAfrican caucasoid galactosemics which is similar to the overall frequency detected in other caucasoid \npopulations. Both the SDSL and the Q188R mutations were detected in the individuals of mixed \nancestry. \n- .......... \nSeveral populations from western, central and southern Africa were screened for the SDSL \nmutation. This mutation was found at low frequencies (± ISE) in western and central Africa, 0.003 \n(+2.5 x 10'3) and 0.003 (±1.96 x 10"), respectively and was detected at a higher frequency (+ 1SE) of \n0.006 (±2.25 x lO"3) in the southeastern Bantu, but was not detected in the San populations screened. \nThis mutation also accounts for approximately 48% of the galactosemia mutations in African \nAmerican galactosemics. Those results suggest an African origin of the S135L mutation. \nThe South African negroid galactosemics and 202 randomly ascertained negroid individuals were \nscreened for the QI88R mutation and &c/RFLP in the GALT gene. The Q188R mutation was not \ndetected in these groups; thus indicating that this mutation was not a major cause of transferase \ngalactosemia in South African negroids. No Sad" alleles were detected in these individuals \nsuggesting that this allele was not associated with the galactosemia mutations in negroids and was \nless frequent in this population than in caucasoids. Seventy South African Indians were screened for \nthe N314D mutation which results in the Duarte electrophoretic phenotype (both Duarte and Los \nAngeles alleles result in this phenotype) is associated with the Duarte variants of galactosemia. The \nN314D mutation was found at the high frequency (± 1 SE) of 0.20 (± 0.033) in this group and this \nmutation was detected in cis with the Sad" allele (Duarte) or in cis with the L218L mutation (Los \nAngeles). \nA previously undescribed mutation, G to A transition at bp 997 in exon 4 of the GALT gene, was \ndiscovered in a randomly ascertained individual from the Central African Rephiic. This mutation is \npredicted to result in the substitution of arginine by glutamine at amino acid IZi, sad did not appear \nto affect the level of GALT activity in red blood cells.

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