Molecular Genetics of Galactosaemia


The three different enzymes of galactose metabolism (galactokinase, galactose‐1‐phosphate uridyltransferase, UDP‐galactose‐4‐epimerase) can be impaired by genetic alterations, leading to three different forms of the genetic disease, galactosaemia. Their clinical outcome can vary from very mild to lethal depending on the enzyme involved, and on the respective gene mutations, but a clear‐cut correlation between genotype and phenotype of patients is not yet known. Understanding the molecular genetics of galactosaemia is essential to correlate the genotype of the patients to their phenotype, and eventually to their clinical outcome. The prediction of the effects of genetic alterations on enzyme structure and functions is just the first step of the long journey towards the final scope: to render clinicians and scientific community the tools to predict the effect of a galactosaemia‐linked mutation on the future quality of life of an affected newborn, in order to provide the best personalised solutions for the treatment.

Key Concepts:

  • Disorders in galactose metabolism in humans caused by hereditary deficiencies of the enzymes in the Leloir pathway can lead to severe and potentially lethal diseases called galactosaemia.

  • Depending on the specific enzyme that is deficient, three types of galactosaemia (Type I, II and III) with varying severity can occur.

  • Newborn screening programmes for galactosaemia are implemented in many developed countries to prevent acute lethality in the affected neonates.

  • The genes encoding the enzymes associated with all types of galactosaemia have been isolated, allowing the determination of the deleterious changes leading to the diseases.

  • Many of the variations seen in the GAL genes are private in nature, although specific changes are prevalent in different ethnic populations.

Keywords: galactosaemia; galactokinase (GALK); galactose‐1‐phosphate uridyltransferase (GALT); UDP‐4‐galactose epimerase (GALE); Inborn error of metabolism (IEM); newborn screening; molecular modelling

Figure 1.

The Leloir pathway of galactose metabolism.

Figure 2.

Structures of the three enzymes of the Leloir pathway. (a) X‐ray structure of human GALK complexed with galactose and MgAMPPNP (an ATP analogue) (PDB file: 1WUU). (b) Model of human GALT complexed with UDP‐galactose (from PDB file 1R3A). (c) X‐ray structure of human GALE complexed with NADH and UDP‐glucose (PDB file: 1EK6). In all structures, the backbone of the protein is in green, and secondary structures are highlighted and coloured in red (helices) and in yellow (sheets). Ligands are shown in stick mode, labelled and colour coded: carbon cyan, oxygen red, nitrogen blue and phosphorus orange. Mg++ ion in (a) is shown as a ball and coloured green. Hydrogen atoms are not shown. These figures have been created using PyMOL (



Acosta PB and Gross KC (1995) Hidden sources of galactose in the environment. European Journal of Pediatrics 154(7 Suppl 2): S87–S92.

Adzhubei IA, Schmidt S, Peshkin L et al. (2010) A method and server for predicting damaging missense mutations. Nature Methods 7(4): 248–249.

Alano A, Almashanu S, Maceratesi P et al. (1997) UDP‐galactose‐4‐epimerase deficiency among African‐Americans: evidence for multiple alleles. Journal of Investigative Medicine 45: 191A.

Berry GT, Nissim I, Lin Z et al. (1995) Endogenous synthesis of galactose in normal men and patients with hereditary galactosaemia. Lancet 346(8982): 1073–1074.

Calderon FR, Nelson L, Dobrowolski P et al. (2007a) Combination of enzyme analysis, allele‐specific PCR and sequencing to detect mutations in the GALT gene. Journal of Inherited Metabolic Disease 30(5): 818.

Calderon FR, Phansalkar AR, Crockett DK, Miller M and Mao R (2007b) Mutation database for the galactose‐1‐phosphate uridyltransferase (GALT) gene. Human Mutation 28(10): 939–943.

Cardini CE and Leloir LF (1953) Enzymic phosphorylation of galactosamine and galactose. Archives of Biochemistry and Biophysics 45(1): 55–64.

Cavallo A and Martin AC (2005) Mapping SNPs to protein sequence and structure data. Bioinformatics 21(8): 1443–1450.

Chhay JS, Vargas CA, McCorvie TJ, Fridovich‐Keil JL and Timson DJ (2008) Analysis of UDP‐galactose 4′‐epimerase mutations associated with the intermediate form of type III galactosaemia. Journal of Inherited Metabolic Disease 31(1): 108–116.

Coffee B, Hjelm LN, DeLorenzo A et al. (2006) Characterization of an unusual deletion of the galactose‐1‐phosphate uridyl transferase (GALT) gene. Genetics in Medicine 8(10): 635–640.

Crews C, Wilkinson KD, Wells L , Perkins C and Fridovich‐Keil JL (2000) Functional consequence of substitutions at residue 171 in human galactose‐1‐phosphate uridylyltransferase. Journal of Biological Chemistry 275(30): 22847–22853.

Darrow RA and Rodstrom R (1966) Subunit association and catalytic activity of uridine diphosphate galactose‐4‐epimerase from yeast. Proceedings of the National Academy of Sciences of the USA 55(1): 205–212.

Dobrowolski SF, Banas RA, Suzow JG, Berkley M and Naylor EW (2003) Analysis of common mutations in the galactose‐1‐phosphate uridyl transferase gene: new assays to increase the sensitivity and specificity of newborn screening for galactosemia. Journal of Molecular Diagnostics 5(1): 42–47.

Drmanac R (2011) The advent of personal genome sequencing. Genetics in Medicine 13(3): 188–190.

Facchiano A and Marabotti A (2010) Analysis of galactosemia‐linked mutations of GALT enzyme using a computational biology approach. Protein Engineering, Design & Selection 23(2): 103–113.

Freer DE, Ficicioglu C and Finegold D (2010) Newborn screening for galactosemia: a review of 5 years of data and audit of a revised reporting approach. Clinical Chemistry 56(3): 437–444.

Fridovich‐Keil JL and Walter J (2008) Galactosemia. In: Valle D, Beaudet AL, Vogelstein B et al. (eds) The Online Metabolic and Molecular Bases of Inherited Diseases‐OMMBID, part 7, chap. 72. New York: McGraw‐Hill (

Jama M, Nelson L, Pont‐Kingdon G, Mao R and Lyon E (2007) Simultaneous amplification, detection, and analysis of common mutations in the galactose‐1‐phosphate uridyl transferase gene. Journal of Molecular Diagnostics 9(5): 618–623.

Jójárt B, Szori M, Izsák R et al. (2011) The effect of a Pro28Thr point mutation on the local structure and stability of human galactokinase enzyme – a theoretical study. Journal of Molecular Modeling 17(10): 2639–2649.

Kalckar HM, Braganca B and Munch‐Petersen HM (1953) Uridyl transferases and the formation of uridine diphosphogalactose. Nature 172(4388): 1038.

Kolosha V, Anoia E, de Cespedes C et al. (2000) Novel mutations in 13 probands with galactokinase deficiency. Human Mutation 15(5): 447–453.

Kozák L, Francová H, Pijácková A et al. (1999) Presence of a deletion in the 5′ upstream region of the GALT gene in Duarte (D2) alleles. Journal of Medical Genetics 36(7): 576–578.

Kumar P, Henikoff S and Ng PC (2009) Predicting the effects of coding non‐synonymous variants on protein function using the SIFT algorithm. Nature Protocols 4(7): 1073–1081.

Lai K, Langley SD, Singh RH et al. (1996) A prevalent mutation for galactosemia among black Americans. Journal of Pediatrics 128(1): 89–95.

Langley SD, Lai K, Dembure PP, Hjelm LN and Elsas LJ (1997) Molecular basis for Duarte and Los Angeles variant galactosemia. American Journal of Human Genetics 60(2): 366–372.

Leloir LF (1951) The enzymatic transformation of uridine diphosphate glucose into a galactose derivative. Archives of Biochemistry and Biophysics 33(2): 186–190.

Li B, Krishnan VG, Mort ME et al. (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25(21): 2744–2750.

Maceratesi P, Daude N, Dallapiccola B et al. (1998) Human UDP‐galactose 4′ epimerase (GALE) gene and identification of five missense mutations in patients with epimerase‐deficiency galactosemia. Molecular Genetics and Metabolism 63(1): 26–30.

Marabotti A and Facchiano AM (2005) Homology modeling studies on human galactose‐1‐phosphate uridylyltransferase and on its galactosemia‐related mutant Q188R provide an explanation of molecular effects of the mutation on homo‐ and heterodimers. Journal of Medicinal Chemistry 48(3): 773–779.

McCorvie TJ, Liu Y, Frazer A et al. (2012) Altered cofactor binding affects stability and activity of human UDP‐galactose 4′‐epimerase: implications for type III galactosemia. Biochimica et Biophysica Acta 1822(10): 1516–1526.

Moult J, Fidelis K, Kryshtafovych A and Tramontano A (2011) Critical assessment of methods of protein structure prediction (CASP)‐‐round IX. Proteins 79(Suppl. 10): 1–5.

Okano Y, Asada M, Fujimoto A et al. (2001) A genetic factor for age‐related cataract: identification and characterization of a novel galactokinase variant, “Osaka,” in Asians. American Journal of Human Genetics 68(4): 1036–1042.

Openo KK, Schulz JM, Vargas CA et al. (2006) Epimerase‐deficiency galactosemia is not a binary condition. American Journal of Human Genetics 78(1): 89–102.

Park HD, Bang YL, Park KU et al. (2007) Molecular and biochemical characterization of the GALK1 gene in Korean patients with galactokinase deficiency. Molecular Genetics and Metabolism 91(3): 234–238.

Park HD, Park KU, Kim JQ et al. (2005) The molecular basis of UDP‐galactose‐4‐epimerase (GALE) deficiency galactosemia in Korean patients. Genetics in Medicine 7(9): 646–649.

Podskarbi T, Kohlmetz T, Gathof BS et al. (1996) Molecular characterization of Duarte‐1 and Duarte‐2 variants of galactose‐1‐phosphate uridyltransferase. Journal of Inherited Metabolic Disease 19(5): 638–644.

Quimby BB, Alano A, Almashanu S et al. (1997) Characterization of two mutations associated with epimerase‐deficiency galactosemia, by use of a yeast expression system for human UDP‐galactose‐4‐epimerase. American Journal of Human Genetics 61(3): 590–598.

Raffan E and Semple RK (2011) Next generation sequencing – implications for clinical practice. British Medical Bulletin 99: 53–71.

Reichardt JK, Packman S and Woo SL (1991) Molecular characterization of two galactosemia mutations: correlation of mutations with highly conserved domains in galactose‐1‐phosphate uridyl transferase. American Journal of Human Genetics 49(4): 860–867.

Singh R, Ram J, Kaur G and Prasad R (2012) Galactokinase deficiency induced cataracts in Indian infants: identification of 4 novel mutations in GALK Gene. Current Eye Research in press (PMID: 22632133).

Stambolian D, Ai Y, Sidjanin D et al. (1995) Cloning of the galactokinase cDNA and identification of mutations in two families with cataracts. Nature Genetics 10(3): 307–312.

Tang M, Facchiano A, Rachamadugu R et al. (2012) Correlation assessment among clinical phenotypes, expression analysis and molecular modeling of 14 novel variations in the human galactose‐1‐phosphate uridylyltransferase gene. Human Mutation 33(7): 1107–1115.

Thoden JB, Timson DJ, Reece RJ and Holden HM (2005) Molecular structure of human galactokinase: implications for type II galactosemia. Journal of Biological Chemistry 280(10): 9662–9670.

Thoden JB, Wohlers TM, Fridovich‐Keil JL and Holden HM (2001) Molecular basis for severe epimerase deficiency galactosemia. X‐ray structure of the human V94M‐substituted UDP‐galactose 4‐epimerase. Journal of Biological Chemistry 276(23): 20617–20623.

Timson DJ (2005) Functional analysis of disease‐causing mutations in human UDP‐galactose 4‐epimerase. FEBS Journal 272(23): 6170–6177.

Timson DJ and Reece RJ (2003) Functional analysis of disease‐causing mutations in human galactokinase. European Journal of Biochemistry 270(8): 1767–1774.

Wedekind JE, Frey PA and Rayment I (1995) Three‐dimensional structure of galactose‐1‐phosphate uridylyltransferase from E. coli at 1.8 A resolution. Biochemistry 34(35): 11049–11061.

Wohlers TM, Christacos NC, Harreman MT and Fridovich‐Keil JL (1999) Identification and characterization of a mutation, in the human UDP‐galactose‐4‐epimerase gene, associated with generalized epimerase‐deficiency galactosemia. American Journal of Human Genetics 64(2): 462–470.

Yang YP, Corley N and Garcia‐Heras J (2002) Molecular analysis in newborns from Texas affected with galactosemia. Human Mutation 19(1): 82–83.

Yue P, Melamud E and Moult J (2006) SNPs3D: candidate gene and SNP selection for association studies. BMC Bioinformatics 7: 166.

Further Reading

Berry GT and Elsas LJ (2011) Introduction to the Maastricht workshop: lessons from the past and new directions in galactosaemia. Journal of Inherited Metabolic Disease 34(2): 249–255.

Bosch AM, Bakker HD, van Gennip AH et al. (2002) Clinical features of galactokinase deficiency: a review of the literature. Journal of Inherited Metabolic Disease 25(8): 629–634.

Elsas LJ (1993) Galactosemia. In: Pagon RA, Bird TD, Dolan CR et al. (eds) GeneReviews. Seattle (WA): University of Washington, Seattle.

Elsas LJ 2nd and Lai K (1998) The molecular biology of galactosaemia. Genetics in Medicine 1(1): 40–48.

Fridovich‐Keil JL (2006) Galactosaemia: the good, the bad, and the unknown. Journal of Cell Physiology 209(3): 701–705.

Holden HM, Rayment I and Thoden JB (2003) Structure and function of enzymes of the Leloir pathway for galactose metabolism. Journal of Biological Chemistry 278(45): 43885–43888.

Segal S (1998) Komrower Lecture. Galactosaemia today: the enigma and the challenge. Journal of Inherited Metabolic Disease 21(5): 455–471.

Segal S (2004) Another aspect of the galactosaemia enigma. Molecular Genetics and Metabolism 81(3): 253–254.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Lai, Kent, Marabotti, Anna, and Mao, Rong(Oct 2012) Molecular Genetics of Galactosaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024323]