Molecular Genetics of Galactosaemia


Galactosaemia is a relatively rare, genetic disease that commonly manifests with cataracts in childhood. More severe forms result in significant developmental abnormalities resulting in physical and cognitive disabilities. Three genes are affected: galactose 1‐phosphate uridylyltransferase (GALT; type I galactosaemia), galactokinase (GALK1; type II) and UDP‐galactose 4'‐epimerase (GALE; type III). Clinical outcomes vary widely in severity and depend on the gene affected, the precise mutation(s) present and the patient's environment. The disease can be diagnosed by altered metabolite levels, reduced enzyme activity and sequencing of the affected gene. In many cases, mutations in one of these three genes result in a protein that is unstable and/or misfolded with consequent reduction in enzymatic activity. Understanding how loss of activity of these enzymes results in the disease phenotypes is a key priority in current research.

Key Concepts

  • Galactosaemia is an inherited metabolic disease affecting the genes encoding enzymes of galactose metabolism.
  • Three types of galactosaemia are recognised depending on which gene is affected.
  • Type I galactosaemia is the most common and affects GALT that encodes galactose 1‐phosphate uridylyltransferase.
  • The severity of symptoms of galactosaemia is highly varied depending on the precise mutation(s) present and the patient's environment.
  • Our understanding of the normal regulation of these genes in humans is incomplete.
  • Diagnosis may be initially made by increased galactose or galactose 1‐phosphate levels.
  • Diagnosis is normally confirmed through measuring enzyme activities and sequencing the affected gene.
  • In many cases, point mutations result in proteins that are misfolded and/or unstable.
  • Our understanding of how mutated genes and altered biochemistry lead to the disease phenotypes is incomplete.
  • Bakers' yeast, fruit flies, nematode worms and mice have all been used successfully as models for galactosaemia.

Keywords: galactose metabolism; inherited metabolic disease; galactokinase; galactose 1‐phosphate; galactose 1‐phosphate uridylyltransferase; UDP‐galactose 4′‐epimerase; diseases of childhood; genetic screening; cataracts; Leloir pathway

Figure 1. The Leloir pathway of galactose metabolism. This pathway converts galactose into glucose 1‐phosphate. This metabolite can be isomerised to glucose 6‐phosphate in a reaction catalysed by phosphoglucomutase (PGM; EC The pathway is sometimes considered to include the isomerisation of β‐d‐galactose to α‐d‐galactose catalysed by galactose mutarotase (aldose 1‐epimerase, GALM; EC To date, no polymorphisms in the GALM gene have been associated with galactosaemia.


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Further Reading

D'acierno A, Facchiano A and Marabotti A (2014) GALT protein database: querying structural and functional features of GALT enzyme. Human Mutation 35: 1060–1067.

Frey PA (1996) The Leloir pathway: a mechanistic imperative for three enzymes to change the stereochemical configuration of a single carbon in galactose. The FASEB Journal: Official publication of the Federation of American Societies for Experimental Biology, 10: 461–470.

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Jumbo‐Lucioni PP, Ryan EL, Hopson M, et al. (2014) Manganese‐based superoxide dismutase mimics modify both acute and long‐term outcome severity in a Drosophila melanogaster model of classic galactosemia. Antioxidants & Redox Signaling 20: 2361–2371.

Lai K, Boxer MB and Marabotti A (2014) GALK inhibitors for classic galactosemia. Future Medicinal Chemistry 6: 1003–1015.

Machado CM, De‐Souza EA, De‐Queiroz AL, et al. (2017) The galactose‐induced decrease in phosphate levels leads to toxicity in yeast models of galactosemia. Biochimica et Biophysica Acta, in press.

Maratha A, Stockmann H, Coss KP, et al. (2016) Classical galactosaemia: novel insights in IgG N‐glycosylation and N‐glycan biosynthesis. European Journal of Human Genetics 24: 976–984.

Timson DJ (2006) The structural and molecular biology of type III galactosemia. IUBMB Life 58: 83–89.

Timson DJ (2016b) The molecular basis of galactosemia ‐ Past, present and future. Gene 589: 133–141.

Waisbren SE, Potter NL, Gordon CM, et al. (2012) The adult galactosemic phenotype. Journal of Inherited Metabolic Disease 35: 279–286.

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Timson, David J(May 2017) Molecular Genetics of Galactosaemia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027224]