European Journal of Pediatrics

, Volume 155, Issue 5, pp 393–397 | Cite as

Three missense mutations in the galactose-1-phosphate uridyltransferase gene of three families with mild galactosaemia

  • Yoon S. Shin
  • Birgit S. Gathof
  • Teodor Podskarbi
  • Marcia Sommer
  • Ricardo Giugliani
  • Ursula Gresser
Metabolic Diseases


Classical galactosaemia caused by deficiency of galactose-1-phosphate uridyltransferase (GALT) is characterized by acute symptoms of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these complications immediately, however, most of these children have a long-term complication of verbal dyspraxia, mental retardation and ovarian failure. The GALT gene was cloned and several mutations including the common Q188R have been reported. In this study the coding region of GALT was amplified by polymerase chain reaction from genomic DNA of classical galactosaemic individuals and characterized by direct sequencing of the products. Three missense mutations were identified in three patients with a mild galactosaemic variant: (1) replacement of threonine-138 by methionine (T138M); (2) replacement of arginine by tryptophan (R259W); and (3) replacement of threonine by alanine (T350A). All three galactosaemic individuals, one girl and two boys, have varying degrees of residual GALT activity in RBC and their galactose-1-phosphate levels decreased much faster than in other galactosaemic patients. These misense mutations occur in regions that are not highly conserved domains.


The study of the molecular basis related to the phenotype variation may indeed help to prognosticate the outcome of patients with classical galactosaemia.

Key words

Galactosaemia Galactose-1-phosphate uridyltransferase gene Missense mutations 



galactose-1-phosphate uridyltransferase




polymerase chain reaction


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Elsas LJ, Dembure PP, Langley S, Paulk EM, Hjelm LN, Friedovich-Keil J (1994) A common mutation associated with the Duarte galactosaemia allele. Am J Hum Genet 54:1030–1036Google Scholar
  2. 2.
    Elsas LJ, Langley S, Steele E, Evinger J, Friedovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP (1995) Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. Am J Hum Genet 56:630–639Google Scholar
  3. 3.
    Gathof BS, Sommer M, Podskarbi T, Reichardt JKV, Braun A, Gresser U, Shin YS (1995) Characterization of two stop codon mutations in the galactose-1-phosphate uridyltransferase gene of three male galactosemic patients with severe clinical manifestation. Hum Genet (in press)Google Scholar
  4. 4.
    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 125:225–227Google Scholar
  5. 5.
    Lemaire HG, Müller-Hill B (1986) Nucleotide sequences of GAL E gene and the GAL T gene ofE. coli. Nucleic Acids Res 14:7705–7711Google Scholar
  6. 6.
    Leslie ND, Immerman EB, Flach JE, Florez M, Friedovich-Keil JL, Elsas LJ (1992) The human galactose-1-phosphate uridyltransferase gene. Genomics 14:474–480Google Scholar
  7. 7.
    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 94:359–363Google Scholar
  8. 8.
    Podskarbi T, Reichardt J, Shin YS (1994) Studies of DNa in galactose-1-phosphate uridyltransferase deficiency and the Duarte variant in Germany. J Inherited Metab Dis 17:149–150Google Scholar
  9. 9.
    Podskarbi T, Shin YS, Reichardt J (1994) Progress toward a genotype/phenotype correlation in classic galactosemia. Proceedings for Soc Study Inborn Error Metabolism, p 201Google Scholar
  10. 10.
    Reichardt JKV (1992) Genetic basis of galactosemia. Hum Mut 1:190–196Google Scholar
  11. 11.
    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 88:2633–2637Google Scholar
  12. 12.
    Reichardt JKV, Levy HL, Woo SLC (1992) Molecular characterization of two galactosemia mutations and one polymorphism: implication for structure-function analysis of human galactose-1-phosphate uridyltransferase. Biochemistry 31:5430–5433Google Scholar
  13. 13.
    Reichardt JKV, Belmont JW, Levy HL, Woo SLC (1992) Characterization of two missense mutations in human GALT: Different molecular mechanisms for galactosemia. Genomics 12:596–600Google Scholar
  14. 14.
    Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chainterminating inhibitors. Proc Natl Acad Sci 74:5463–5467Google Scholar
  15. 15.
    Schweitzer S, Shin YS, Jakobs C, Brodehl J (1993) Long-term outcome in 134 patients with galactosemia. Eur J Pediatr 152:36–43Google Scholar
  16. 16.
    Shin YS (1991) Galactose metabolism and disorders of galactose metabolism. In: Hommes FA (ed) Techniques in diagnostic human biochemical genetics. Wiley-Liss Inc, New York, pp 267–283Google Scholar
  17. 17.
    Shin YS, Niedermeier HP, Endres W, Schaub J, Weidinger S (1985) Agarose gel isoelectrofocusing of UDP-galactose pyrophosphorylase and galactose-1-phosphate uridyltransferase. Developmental aspects of UDP-galactose pyrophosphorylase. Clin Chim Acta 166:27–35Google Scholar
  18. 18.
    Sommer M, Gathof BS, Podskarbi T, Giugliani R, Kleinlein B, Shin YS (1995) Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosemia variants. J Inherited Metab Dis 18: 567–576Google Scholar
  19. 19.
    Tajima M, Nogi Y, Fukasawa T (1985) Primary structure of the Saccharomyces cerevisiae GAL7 gene. Yeast 1:67–77Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Yoon S. Shin
    • 1
  • Birgit S. Gathof
    • 2
  • Teodor Podskarbi
    • 3
  • Marcia Sommer
    • 4
  • Ricardo Giugliani
    • 4
  • Ursula Gresser
    • 2
  1. 1.Universitäts-KinderkrankenhausMünchenGermany
  2. 2.Medizinische PoliklinikMünchenGermany
  3. 3.Medizinisch Immunologische LaboratorienMünchenGermany
  4. 4.Medical Genetics UnitHCPAPorto AlegreBrazil

Personalised recommendations