Abstract
Classical galactosemia is a genetic disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. The Q188R and N314D mutations are the most frequently cited GALT gene mutations. N314D is further associated with two variants, Duarte 1 and Duarte 2. Nevertheless, no reports are available on the clinical and molecular spectrum of galactosemia from the Indian population. The present study was designed to establish the frequency of these two most common mutations and their variants in Indian galactosemia patients so as to determine a single most common mutation/polymorphism for establishing the DNA-based diagnosis of galactosemia. Three alleles were found to be present at a frequency of 0.036 (Q188R), 0.40 (N314D), and 0.39 (D2); no D1 alleles were found. A significantly higher frequency of the Duarte 2 allele in our population suggests the presence of a milder form of galactosemia, which can be well managed by early diagnosis and dietary management.
Similar content being viewed by others
References
Ashino J, Okano Y, Suyama I, Yamazaki T, Yoshino M, Furuyama J, Lin H, Reichardt J, Ishiki G (1995) Molecular characterization of galactosemia (type 1) mutations in Japanese. Hum Mutat 6:36–43
Beutler E, Baluda MC (1966) A simple spot screening test for galactosemia. J Lab Clin Med 68:137–141
Daly AK, Steen VM, Fairbrother KS, Idle JR (1996) CYP2D6 multiallelism. Method Enzymol 272:199–210
Elsas LJ, Fridovich-Keil JL, Leslie N (1993) Galactosemia: a molecular approach to the enigma. Int Pediatr 8:101–109
Elsas LJ, Langley S, Steele E, Evinger J, Fridovich-Keil JL, Brown A, Singh R, Fernhoff P, Hjelm LN, Dembure PP (1995a) Galactosemia: a strategy to identify new biochemical phenotypes and molecular genotypes. Am J Hum Genet 56:630–639
Elsas LJ, Palk EM, Langley S, Hjelm LN, Dembure PP (1995b) A molecular approach to galactosemia. Eur J Pediatr 154:S21–S27
Elsas LJ, Webb AL, Langley SD (2002) Characterization of a carbohydrate response element regulating the gene for human galactose-1-phosphate uridyltransferase. Mol Genet Metab 76:287–296
Field TL, Reznikoff WS, Frey PA (1989) Galactose-l-phosphate uridylyltransferase: identification of histidine-164 and histidine-166 as critical residues by site-directed mutagenesis. Biochemistry 28:2094–2099
Frey PA (1996) The Leloir pathway: a mechanistic imperative for three enzymes to change the stereochemical configuration of a single carbon in galactose. FASEB J 10:461–470
Fridovich-Keil J, Jinks-Robertson S (1993) A yeast expression system for human galactose-1-phosphate uridylyltransferase. Proc Natl Acad Sci USA 90:398–402
Gathof B, Sommer M, Podskarbi R, Reichardt J, Braum 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 96:721–725
Goldstein N, Cohen Y, Pode-Shakked B, Sigalov E, Vilensky B, Peleg L, Anikster Y (2011) The GALT rush: high carrier frequency of an unusual deletion mutation of the GALT gene in the Ashkenazi population. Mol Genet Metab 102:157–160
Greber-Platzer S, Guldberg P, Scheibenreiter S, Item C, Schuller E, Strobl W (1997) Molecular heterogeneity of classical and Duarte galactosemia: mutation analysis by denaturating gradient gel electrophoresis. Hum Mutat 10(1):49–57
Holton JB, Walter JH, Tyfield LA (2001) Galactosemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw-Hill, New York, pp 1553–1583
Horvath A, Gyurus P, Kis A, Laszlo A, Schuler A, Kosztolanyi G, Melegh B (2000) Distribution of Q188R and N314D mutations in the Hungarian galactosemic population. Hum Mutat 16:91
Kirkman HW, Maxwell ES (1960) Enzymatic estimation of erythrocytic galactose-l-phosphate. J Lab Clin Med 56:161–166
Kozak L, Francova H, Pijackova A, Macku J, Stastna S, Peskovova K, Martincova O, Krijt J (1999) Presence of a deletion in the 5′ upstream region of the GALT gene in Duarte (D2) alleles. J Med Genet 36:576–578
Kozak L, Francova H, Fajkusov L, Pijackova A, Macku JMS, Peskovova K, Martincová O, Krijt J, Bzdúch V (2000) Mutation analysis of the GALT gene in Czech and Slovak galactosemia populations: identification of six novel mutations, including a stop codon mutation (X380R). Hum Mutat 15:206
Lai K, Langley S, Dembure P, Hjelm L, Elsas L (1998) Duarte allele impairs biostability of galactose-1-phosphate uridyltransferase in human lymphoblasts. Hum Mutat 11:28–38
Langley S, Lai K, Dembure P, Hjelm L, Elsas L (1997) Molecular basis for Duarte and Los Angeles variant galactosemia. Am J Hum Genet 60:366–372
Murphy M, Sexton D, O’Neill C, Croke DT, Mayne PD, Naughten ER (1996) Frequency distribution of the Q188R mutation in the Irish galactosemic population. J Inher Metab Dis 19:217–219
Ng WG, Bergren WR, Donnell GN (1973) A new variant of galactose-1-phosphate uridyltransferase in man: the Los Angeles variant. Ann Hum Genet 37:1–8
Podskarbi T, Reichardt J, Shin YS (1994) Studies of DNA in galactose-1-phosphate uridyltransferase deficiency and the Duarte variant in Germany. J Inher Metab Dis 17:149–150
Reichardt J, Woo S (1991) Molecular basis of galactosemia: mutations and polymorphisms in the gene encoding human galactose-1-phosphate uridylyltransferase. Proc Natl Acad Sci USA 88:2633–2637
Trbusek M, Francova H, Kozak L (2001) Galactosemia: deletion in the 5′ upstream region of the GALT gene reduces promoter efficiency. Hum Genet 109:117–120
Tyfield L, Reichardt J, Fridoviuch-Keil J, Croke DT, Elsas LJ, Strobl W, Kozak L, Coskun T, Novelli G, Okano Y, Zekanowski C, Shin Y, Boleda MD (1999) Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat 13:417–430
Acknowledgments
We are indebted to the parents of the patients for their cooperation. We would also like to acknowledge the complete financial assistance extended by the Department of Biotechnology, Ministry of Science and Technology, Government of India (BT/PR/6344/MED/14/783/2005).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Singh, R., Thapa, B.R., Kaur, G. et al. Frequency Distribution of Q188R, N314D, Duarte 1, and Duarte 2 GALT Variant Alleles in an Indian Galactosemia Population. Biochem Genet 50, 871–880 (2012). https://doi.org/10.1007/s10528-012-9527-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-012-9527-z