Molecular Genetics of Galactosaemia

Abstract

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 5.4.2.2). 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 5.1.3.3). To date, no polymorphisms in the GALM gene have been associated with galactosaemia.
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References

Alano A, Almashanu S, Chinsky JM, et al. (1998) Molecular characterization of a unique patient with epimerase‐deficiency galactosaemia. Journal of Inherited Metabolic Disease 21: 341–350.

Bergsma DJ, Ai Y, Skach WR, et al. (1996) Fine structure of the human galactokinase GALK1 gene. Genome Research 6: 980–985.

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: 629–634.

Brokate‐Llanos AM, Monje JM, Murdoch Pdel S and Munoz MJ (2014) Developmental defects in a Caenorhabditis elegans model for type III galactosemia. Genetics 198: 1559–1569.

Cai D, Yuan M, Liu H, et al. (2017) Epigenetic and SP1‐mediated regulation is involved in the repression of galactokinase 1 gene in the liver of neonatal piglets born to betaine‐supplemented sows. European Journal of Nutrition, in press.

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

Cheung KL, Tang NL, Hsiao KJ, et al. (1999) Classical galactosaemia in Chinese: a case report and review of disease incidence. Journal of Paediatrics and Child Health 35: 399–400.

Coman DJ, Murray DW, Byrne JC, et al. (2010) Galactosemia, a single gene disorder with epigenetic consequences. Pediatric Research 67: 286–292.

Coss KP, Byrne JC, Coman DJ, et al. (2012) IgG N‐glycans as potential biomarkers for determining galactose tolerance in classical galactosaemia. Molecular Genetics and Metabolism 105: 212–220.

Coss KP, Hawkes CP, Adamczyk B, et al. (2014) N‐glycan abnormalities in children with galactosemia. Journal of Proteome Research 13: 385–394.

Daenzer JM, Sanders RD, Hang D and Fridovich‐Keil JL (2012) UDP‐galactose 4'‐epimerase activities toward UDP‐Gal and UDP‐GalNAc play different roles in the development of Drosophila melanogaster. PLoS Genetics 8: e1002721.

Daenzer JM, Jumbo‐Lucioni PP, Hopson ML, et al. (2016) Acute and long‐term outcomes in a Drosophila melanogaster model of classic galactosemia occur independently of galactose‐1‐phosphate accumulation. Disease Models & Mechanisms 9: 1375–1382.

Daenzer JM and Fridovich‐Keil JL (2017) Drosophila melanogaster models of galactosemia. Current Topics in Developmental Biology 121: 377–395.

Daude N, Gallaher TK, Zeschnigk M, et al. (1995) Molecular cloning, characterization, and mapping of a full‐length cDNA encoding human UDP‐galactose 4'‐epimerase. Biochemical and Molecular Medicine 56: 1–7.

De‐Souza EA, Pimentel FS, Machado CM, et al. (2014) The unfolded protein response has a protective role in yeast models of classic galactosemia. Disease Models & Mechanisms 7: 55–61.

Devi YS, Shehu A, Stocco C, et al. (2009) Regulation of transcription factors and repression of Sp1 by prolactin signaling through the short isoform of its cognate receptor. Endocrinology 150: 3327–3335.

Elsas LJ, Lai K, Saunders CJ and Langley SD (2001) Functional analysis of the human galactose‐1‐phosphate uridyltransferase promoter in Duarte and LA variant galactosemia. Molecular Genetics and Metabolism 72: 297–305.

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

Halperin J, Devi YS, Elizur S, et al. (2008) Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect. Molecular Endocrinology 22: 513–522.

Isselbacher KJ, Anderson EP, Kurahashi K and Kalckar HM (1956) Congenital galactosemia, a single enzymatic block in galactose metabolism. Science (New York, N.Y.) 123: 635–636.

Jumbo‐Lucioni PP, Hopson ML, Hang D, et al. (2013) Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia. Disease Models & Mechanisms 6: 84–94.

Lai K, Elsas LJ and Wierenga KJ (2009) Galactose toxicity in animals. IUBMB Life 61: 1063–1074.

Leslie ND and Bai S (2001) Functional analysis of the mouse galactose‐1‐phosphate uridyl transferase (GALT)promoter. Molecular Genetics and Metabolism 72: 31–38.

Mccorvie TJ and Timson DJ (2011) Structural and molecular biology of type I galactosemia: disease‐associated mutations. IUBMB Life 63: 949–954.

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: 1516–1526.

Mccorvie TJ, Gleason TJ, Fridovich‐Keil JL and Timson DJ (2013) Misfolding of galactose 1‐phosphate uridylyltransferase can result in type I galactosemia. Biochimica et Biophysica Acta 1832: 1279–1293.

Mccorvie TJ and Timson DJ (2013) In silico prediction of the effects of mutations in the human UDP‐galactose 4'‐epimerase gene: towards a predictive framework for type III galactosemia. Gene 524: 95–104.

Mccorvie TJ, Kopec J, Pey AL, et al. (2016) Molecular basis of classic galactosemia from the structure of human galactose 1‐phosphate uridylyltransferase. Human Molecular Genetics 25: 2234–2244.

Mulhern ML, Madson CJ, Danford A, et al. (2006) The unfolded protein response in lens epithelial cells from galactosemic rat lenses. Investigative Ophthalmology & Visual Science 47: 3951–3959.

Murphy M, Mchugh B, Tighe O, et al. (1999) Genetic basis of transferase‐deficient galactosaemia in Ireland and the population history of the Irish Travellers. European Journal of Human Genetics 7: 549–554.

Narravula A, Garber KB, Askree SH, Hegde M and Hall PL (2017) Variants of uncertain significance in newborn screening disorders: implications for large‐scale genomic sequencing. Genetics in Medicine 19: 77–82.

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: 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: 89–102.

Pey AL, Padin‐Gonzalez E, Mesa‐Torres N and Timson DJ (2014) The metastability of human UDP‐galactose 4′‐epimerase (GALE) is increased by variants associated with type III galactosemia but decreased by substrate and cofactor binding. Archives of Biochemistry and Biophysics 562: 103–114.

Prodan‐Zitnik I, Karas‐Kuzelicki N and Lukac‐Bajalo J (2009) Positive correlation between galactose‐1‐phosphate uridyltransferase (GALT) and UDP‐galactose‐4′‐epimerase (GALE) activities. Clinical Biochemistry 42: 1561–1564.

Reichardt JK and Berg P (1988) Cloning and characterization of a cDNA encoding human galactose‐1‐phosphate uridyl transferase. Molecular Biology & Medicine 5: 107–122.

Rubio‐Gozalbo ME, Gubbels CS, Bakker JA, et al. (2010) Gonadal function in male and female patients with classic galactosemia. Human Reproduction Update 16: 177–188.

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: 307–312.

Staubach S, Muller S, Pekmez M and Hanisch FG (2017) Classical galactosemia: insight into molecular pathomechanisms by differential membrane proteomics of fibroblasts under galactose stress. Journal of Proteome Research 16: 516–527.

Suzuki M, West C and Beutler E (2001) Large‐scale molecular screening for galactosemia alleles in a pan‐ethnic population. Human Genetics 109: 210–215.

Tang M, Siddiqi A, Witt B, et al. (2014) Subfertility and growth restriction in a new galactose‐1 phosphate uridylyltransferase (GALT) ‐ deficient mouse model. European Journal of Human Genetics 22: 1172–1179.

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

Timson DJ (2007) Galactose metabolism in Saccharomyces cerevisiae. Dynamic Biochemistry, Process Biotechnology and Molecular Biology 1: 63–73.

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

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

Varela‐Lema L, Paz‐Valinas L, Atienza‐Merino G, et al. (2016) Appropriateness of newborn screening for classic galactosaemia: a systematic review. Journal of Inherited Metabolic Disease 39: 633–649.

Von Reuss A (1908) Zuckerausscheidung im Säuglingsalter. Wiener Medizinische Wochenschrift 58: 799–801.

Welling L, Bernstein LE, Berry GT, et al. (2016) International clinical guideline for the management of classical galactosemia: diagnosis, treatment, and follow‐up. Journal of Inherited Metabolic Disease 40: 171–176.

Wen Y, Qin J, Deng Y, et al. (2014) The critical role of UDP‐galactose‐4‐epimerase in osteoarthritis: modulating proteoglycans synthesis of the articular chondrocytes. Biochemical and Biophysical Research Communications 452: 906–911.

Yang F, Agulian T, Sudati JE, Rhoads DB and Levitsky LL (2004) Developmental regulation of galactokinase in suckling mouse liver by the Egr‐1 transcription factor. Pediatric Research 55: 822–829.

Zhang ZF, FAN SH, Zheng YL, et al. (2009) Purple sweet potato color attenuates oxidative stress and inflammatory response induced by D‐galactose in mouse liver. Food and Chemical Toxicology: An International Journal published for the British Industrial Biological Research Association 47: 496–501.

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.

Holden HM, Thoden JB, Timson DJ and Reece RJ (2004) Galactokinase: structure, function and role in type II galactosemia. Cellular and Molecular Life Sciences: CMLS 61: 2471–2484.

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. http://www.els.net [doi: 10.1002/9780470015902.a0027224]