Molecular Genetics of Galactosaemia

Abstract

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 (http://www.pymol.org).

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Further Reading

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

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