Glycine decarboxylase deficiency causes neural tube defects and features of non-ketotic hyperglycinemia in mice.
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.
Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK.
Yun Jin
YJ
Pai
Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK.
Kit-Yi
KY
Leung
Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK.
Dawn
D
Savery
Newborn Screening and Biochemical Genetics, Birmingham Children's Hospital, Birmingham B4 6NH, UK.
Tim
T
Hutchin
1] Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK [2] Department of Chemical Pathology, Institute of Child Health, University College London, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
Helen
H
Prunty
1] Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK [2] Department of Chemical Pathology, Institute of Child Health, University College London, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
Simon
S
Heales
Department of Biochemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada A1B3X9.
Margaret E
ME
Brosnan
Department of Biochemistry, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada A1B3X9.
John T
JT
Brosnan
Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK.
Andrew J
AJ
Copp
Birth Defects Research Centre and Developmental Biology &Cancer Programme, Institute of Child Health, University College London, London WC1N 1EH, UK.
Nicholas D E
ND
Greene
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism; D005561:Formates / Q000494:pharmacology; D005697:Galactosides; D008401:Gas Chromatography-Mass Spectrometry; D005838:Genotype; D005998:Glycine / Q000378:metabolism; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000172:deficiency*; D020158:Hyperglycinemia, Nonketotic / Q000201:enzymology* / Q000209:etiology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007211:Indoles; D051379:Mice; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000201:enzymology* / Q000209:etiology* / Q000517:prevention & control; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
D017931:DNA Primers; D005561:Formates; D005697:Galactosides; D007211:Indoles; C030544:formic acid; D005492:Folic Acid; D050841:Glycine Dehydrogenase (Decarboxylating); D005998:Glycine; C044888:5-bromo-4-chloro-3-indolyl beta-galactoside