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.
Highlights
Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism
Gldc is an atypical PLP-dependent amino-acid decarboxylase in that the aminomethyl moiety of glycine is not released as methylamine but transferred to Gcsh[1]
Our findings highlight the significance of this mechanism in that both functions of Gldc, glycine decarboxylation and transfer of a one-carbon group into folate one-carbon metabolism (FOCM), appear to be essential for normal central nervous system (CNS) development
Summary
Glycine decarboxylase (GLDC) acts in the glycine cleavage system to decarboxylate glycine and transfer a one-carbon unit into folate one-carbon metabolism. Glycine decarboxylase (GLDC; glycine dehydrogenase (decarboxylating)), encoded by GLDC, catalyses the first step of glycine cleavage, in which one carbon is released as CO2 This reaction occurs in the presence of an accessory protein, GCS H-protein (GCSH), to which the aminomethyl moiety is transferred[1]. Loss-of-function mutations in GCS-encoding genes cause the rare autosomal recessive disease, non-ketotic hyperglycinemia (NKH), known as glycine encephalopathy In addition to causing NKH, mutations in GCS-encoding genes have been proposed to predispose to neural tube defects (NTDs), common birth defects of the developing central nervous system (CNS), which include spina bifida and anencephaly[9,10].
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