Abstract
Classical galactosemia, which is caused by deficiency of galactose-1-phosphate uridyltransferase, is characterized by acute problems of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these symptoms immediately; however, the long-term complications, such as mental retardation and ovarian failures are major problems in most of these patients. In order to investigate the molecular basis for phenotype variation in galactosemia, we have screened the most common mutation in the GALT gene, Q188R. We have further examined those patients who are heterozygous for Q188R or negative for this mutation by SSCP analysis and direct sequencing. In three male patients, we have identified, for the first time, two stop-codon mutations in the GALT gene, G212X (exon 7) and E340X (exon 10). Two patients of 8 and 28 years of age, respectively, who are compound heterozygotes for Q188R and G212X, have severe mental retardation and their general clinical condition is more severe than that of patients with missense mutations. The third patient, who is 8 years of age and who is homozygous for E340X, the N314D polymorphism and a silent substitution L218L, presents with a relatively normal physical and mental condition to date.
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Elsas LJ, Dembure PP, Langley S, Paulk EM, Hjelm LN, Fridovich-Keil J (1944) A common mutation associated with the Duarte galactosemia allele. Am J Hum Genet 54:1030–1036
Kaufman FR, Reichardt JKV, Ng WG, Manis FR, McBride-Chang C, Wolff JA (1994) Correlation of cognitive, neurologic and ovarian outcome with the Q188R mutation of the galactose-1-phosphate uridyltransferase gene. J Pediatr 125:225–227
Leslie ND, Immerman EB, Flach JE, Florez M, Fridovich-Keil JL, Elsas LJ (1992) The human galactose-1-phosphate uridyltransferase gene. Genomics 14:474–480
Ng WG, Xu YK, Kaufman FR, Donnell GN, Wolff J, Allen RJ, Koritala S, Reichardt JKV (1994) Biochemical and molecular studies of 132 patients with galactosemia. Hum Genet 94:359–363
Podskarbi T, Reichardt J, Shin YS (1994a) Studies of DNA in galactose-1-phosphate uridyltransferase deficiency and the Duarte variant in Germany. J Inherit Metab Dis 17:149–150
Podskarbi T, Shin YS, Reichardt J (1994b) Progress toward a genotype/phenotype correlation in classic galactosemia. Kluwer Academic Publishers, Lancaster, UK (abstract). Proc Soc Study Inborn Error Metab, pp 201
Reichardt JKV (1992) Genetic basis of galactosemia. Hum Mutat 1:190–196
Reichardt JKV, Woo SLC (1991) Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridyltransferase. Proc Natl Acad Sci USA 88:2633–2637
Reichardt JKV, Levy HL, Woo SLC (1992a) Molecular characterization of two galactosemia mutations and one polymorphism: implication for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry 31:5430–5433
Reichardt JKV, Belmont JW, Levy HL, Woo SLC (1992b) Characterization of two missense mutations in human GALT: different molecular mechanisms for galactosemia. Genomics 12:596–600
Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5434–5467
Schweitzer S, Shin Y, Jakobs C, Brodehl J (1993) Long-term outcome in 134 patients with galactosemia. Eur J Pediatr 152:36–43
Shin YS (1991) Galactose metabolism and disorders of galactose metabolism. In: Hommes FA (ed) Techniques in diagnostic human biochemical genetics. Wiley-Liss, New York, pp 267–283
Shin YS, Gathof BS, Sommer M, Giugliani R, Gresser U, Podskarbi T (1995) Three missence mutations in the galactose-1-phoshate uridyltransferase gene which encode mild galactosemia variants. Eur J Pediatr (in press)
Sommer M, Gathof BS, Giugliani R, Podskarbi T, Gresser U, Shin YS (1995) Two missense mutations of the galactose-1-phosphate uridyltransferase gene in two families with mild galactosemia. J Inher Metab Dis (in press)
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Gathof, B.S., Sommer, M., Podskarbi, T. et al. Characterization of two stop codon mutations in the galactose-1-phosphate uridyltransferase gene of three male galactosemic patients with severe clinical manifestation. Hum Genet 96, 721–725 (1995). https://doi.org/10.1007/BF00210306
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DOI: https://doi.org/10.1007/BF00210306