A search for transferase galactosemia genes in the South African negroid population

Abstract

Transferase galactosemia is an autosomal recessively inherited disorder caused by a block in the conversion of galactose to glucose. Manifestations include jaundice, vomiting, cataracts, mental retardation, speech abnormalities and poor growth. This disorder is due to a deficiency of galactose- 1-phosphate uridyl transferase (GAIT), an enzyme which catalyses the conversion of uridyldisphosphoglucose (UDPG) and galactose-l-phosphate to uridyldisphosphogalactose (UDPGal) and glucose-1-phosphate. The GALT gene has been mapped and 50 mutations have been reported in this; gene to date. The aims of this project were to identity and characterise galactosemia-causing mutations in the South African negroid population and to determine the frequency of these mutations in order to estimate the incidence of transferase galactosemia in the South African negroid population. Twentysix negroid patients and one obligate carrier were investigated and the SI35L mutation was found to account for approximately 91% (48/53) of galactosemia alleles in this group. The estimated S135L allele carrier frequency in 600 healthy unrelated negroid individuals (1/75) was used in conjunction with the proportion of non-S135L galactosemia alleles present in galactosemics to arrive at an estimated galactosemia incidence of 1 per 18 455 births. This is over three times the estimated world average of one per 70 000. Three caucasoid galactosemia patients, one galactosemic patient of mixed ancestry and two obligate carriers (one caucasoid and one of mixed ancestry) were screened for mutations in the GALT gene. The Q188R mutation was found to account for 57% (4/7) of the galactosemia mutations in the South African caucasoid galactosemics which is similar to the overall frequency detected in other caucasoid populations. Both the SDSL and the Q188R mutations were detected in the individuals of mixed ancestry. - .......... Several populations from western, central and southern Africa were screened for the SDSL mutation. This mutation was found at low frequencies (± ISE) in western and central Africa, 0.003 (+2.5 x 10'3) and 0.003 (±1.96 x 10""), respectively and was detected at a higher frequency (+ 1SE) of 0.006 (±2.25 x lO"3) in the southeastern Bantu, but was not detected in the San populations screened. This mutation also accounts for approximately 48% of the galactosemia mutations in African American galactosemics. Those results suggest an African origin of the S135L mutation. The South African negroid galactosemics and 202 randomly ascertained negroid individuals were screened for the QI88R mutation and &c/RFLP in the GALT gene. The Q188R mutation was not detected in these groups; thus indicating that this mutation was not a major cause of transferase galactosemia in South African negroids. No Sad" alleles were detected in these individuals suggesting that this allele was not associated with the galactosemia mutations in negroids and was less frequent in this population than in caucasoids. Seventy South African Indians were screened for the N314D mutation which results in the Duarte electrophoretic phenotype (both Duarte and Los Angeles alleles result in this phenotype) is associated with the Duarte variants of galactosemia. The N314D mutation was found at the high frequency (± 1 SE) of 0.20 (± 0.033) in this group and this mutation was detected in cis with the Sad" allele (Duarte) or in cis with the L218L mutation (Los Angeles). A previously undescribed mutation, G to A transition at bp 997 in exon 4 of the GALT gene, was discovered in a randomly ascertained individual from the Central African Rephiic. This mutation is predicted to result in the substitution of arginine by glutamine at amino acid IZi, sad did not appear to affect the level of GALT activity in red blood cells.