Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice

Yun Jin Pai, Kit-Yi Leung, Dawn Savery, Tim Hutchin, Helen Prunty, Simon Heales, Margaret E. Brosnan, John T. Brosnan, Andrew J. Copp and Nicholas D.E. Greene ()
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Yun Jin Pai: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Kit-Yi Leung: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Dawn Savery: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Tim Hutchin: Newborn Screening and Biochemical Genetics, Birmingham Children’s Hospital
Helen Prunty: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Simon Heales: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Margaret E. Brosnan: Memorial University of Newfoundland
John T. Brosnan: Memorial University of Newfoundland
Andrew J. Copp: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London
Nicholas D.E. Greene: Birth Defects Research Centre and Developmental Biology & Cancer Programme, Institute of Child Health, University College London

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. GLDC mutations cause a rare recessive disease non-ketotic hyperglycinemia (NKH). Mutations have also been identified in patients with neural tube defects (NTDs); however, the relationship between NKH and NTDs is unclear. We show that reduced expression of Gldc in mice suppresses glycine cleavage system activity and causes two distinct disease phenotypes. Mutant embryos develop partially penetrant NTDs while surviving mice exhibit post-natal features of NKH including glycine accumulation, early lethality and hydrocephalus. In addition to elevated glycine, Gldc disruption also results in abnormal tissue folate profiles, with depletion of one-carbon-carrying folates, as well as growth retardation and reduced cellular proliferation. Formate treatment normalizes the folate profile, restores embryonic growth and prevents NTDs, suggesting that Gldc deficiency causes NTDs through limiting supply of one-carbon units from mitochondrial folate metabolism.

Date: 2015
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DOI: 10.1038/ncomms7388

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