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Am J Hum Genet. Oct 1991; 49(4): 860–867.
PMCID: PMC1683190

Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose-1-phosphate uridyl transferase.

Abstract

Galactosemia is an autosomal recessive disorder of human galactose metabolism caused by deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT). The molecular basis of this disorder is at present not well understood. We report here two missense mutations which result in low or undetectable enzymatic activity. First, we identified at nucleotide 591 a transition which substitutes glutamine 188 by arginine. The mutated glutamine is not only highly conserved in evolution (conserved also in Escherichia coli and Saccharomyces cerevisiae), but is also two amino acid residues downstream from the active site histidine-proline-histidine triad and results in about 10% of normal enzymatic activity. The arginine 188 mutation is the most common galactosemia mutation characterized to date. It accounts for one-fourth of the galactosemia alleles studied. Second, we report the substitution of arginine 333 by tryptophan, caused by a transition at nucleotide 1025. The area surrounding this missense mutation is the most highly conserved domain in the homologous enzymes from E. coli, yeast, and humans, and this mutation results in undetectable enzymatic activity, suggesting that this is a severe mutation. This second mutation appears to be rare, since it was found only in the patient we sequenced. Our data provide further evidence for the heterogeneity of galactosemia at the molecular level, heterogeneity which might be related to the variable clinical outcome observed in this disorder.

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Selected References

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  • Böhles H, Wenzel D, Shin YS. Progressive cerebellar and extrapyramidal motor disturbances in galactosaemic twins. Eur J Pediatr. 1986 Oct;145(5):413–417. [PubMed]
  • Cooper DN, Youssoufian H. The CpG dinucleotide and human genetic disease. Hum Genet. 1988 Feb;78(2):151–155. [PubMed]
  • Dobbie JA, Holton JB, Clamp JR. Defective galactosylation of proteins in cultured skin fibroblasts from galactosaemic patients. Ann Clin Biochem. 1990 May;27(Pt 3):274–275. [PubMed]
  • Field TL, Reznikoff WS, Frey PA. Galactose-1-phosphate uridylyltransferase: identification of histidine-164 and histidine-166 as critical residues by site-directed mutagenesis. Biochemistry. 1989 Mar 7;28(5):2094–2099. [PubMed]
  • Flach JE, Reichardt JK, Elsas LJ., 2nd Sequence of a cDNA encoding human galactose-1-phosphate uridyl transferase. Mol Biol Med. 1990 Aug;7(4):365–369. [PubMed]
  • Friedman JH, Levy HL, Boustany RM. Late onset of distinct neurologic syndromes in galactosemic siblings. Neurology. 1989 May;39(5):741–742. [PubMed]
  • Kaufman FR, Xu YK, Ng WG, Donnell GN. Correlation of ovarian function with galactose-1-phosphate uridyl transferase levels in galactosemia. J Pediatr. 1988 May;112(5):754–756. [PubMed]
  • Kelley RI, Feinberg DM, Segal S. Galactose-1-phosphate uridyl transferase in density-fractionated erythrocytes. Studies of normal and mutant enzymes. Hum Genet. 1989 May;82(2):99–103. [PubMed]
  • Lemaire HG, Müller-Hill B. Nucleotide sequences of the gal E gene and the gal T gene of E. coli. Nucleic Acids Res. 1986 Oct 10;14(19):7705–7711. [PMC free article] [PubMed]
  • Lo W, Packman S, Nash S, Schmidt K, Ireland S, Diamond I, Ng W, Donnell G. Curious neurologic sequelae in galactosemia. Pediatrics. 1984 Mar;73(3):309–312. [PubMed]
  • Ng WG, Xu YK, Kaufman FR, Donnell GN. Deficit of uridine diphosphate galactose in galactosaemia. J Inherit Metab Dis. 1989;12(3):257–266. [PubMed]
  • Reichardt JK, Berg P. Conservation of short patches of amino acid sequence amongst proteins with a common function but evolutionarily distinct origins: implications for cloning genes and for structure-function analysis. Nucleic Acids Res. 1988 Sep 26;16(18):9017–9026. [PMC free article] [PubMed]
  • Reichardt JK, Woo SL. Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase. Proc Natl Acad Sci U S A. 1991 Apr 1;88(7):2633–2637. [PMC free article] [PubMed]
  • Rogers S, Holtzapple PG, Mellman WJ, Segal S. Characteristics of galactose-1-phosphate uridyl transferase in intestinal mucosa of normal and galactosemic humans. Metabolism. 1970 Sep;19(9):701–708. [PubMed]
  • Russell JD, DeMars R. UDP-glucose: alpha-D-galactose-1-phosphate uridylytransferase activity in cultured human fibroblasts. Biochem Genet. 1967 Jun;1(1):11–24. [PubMed]
  • Segal S, Rogers S, Holtzapple PG. Liver galactose-1-phosphate uridyl transferase: activity in normal and galactosemic subjects. J Clin Invest. 1971 Mar;50(3):500–506. [PMC free article] [PubMed]
  • Gitzelmann R, Steinmann B. Galactosemia: how does long-term treatment change the outcome? Enzyme. 1984;32(1):37–46. [PubMed]
  • Tajima M, Nogi Y, Fukasawa T. Primary structure of the Saccharomyces cerevisiae GAL7 gene. Yeast. 1985 Sep;1(1):67–77. [PubMed]
  • Waisbren SE, Norman TR, Schnell RR, Levy HL. Speech and language deficits in early-treated children with galactosemia. J Pediatr. 1983 Jan;102(1):75–77. [PubMed]

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