PMID:22171071

Citation	Narisawa, A, Komatsuzaki, S, Kikuchi, A, Niihori, T, Aoki, Y, Fujiwara, K, Tanemura, M, Hata, A, Suzuki, Y, Relton, CL, Grinham, J, Leung, KY, Partridge, D, Robinson, A, Stone, V, Gustavsson, P, Stanier, P, Copp, AJ, Greene, ND, Tominaga, T, Matsubara, Y and Kure, S (2012) Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans. Hum. Mol. Genet. 21:1496-503
Abstract	Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects of the central nervous system. The complex multigenic causation of human NTDs, together with the large number of possible candidate genes, has hampered efforts to delineate their molecular basis. Function of folate one-carbon metabolism (FOCM) has been implicated as a key determinant of susceptibility to NTDs. The glycine cleavage system (GCS) is a multi-enzyme component of mitochondrial folate metabolism, and GCS-encoding genes therefore represent candidates for involvement in NTDs. To investigate this possibility, we sequenced the coding regions of the GCS genes: AMT, GCSH and GLDC in NTD patients and controls. Two unique non-synonymous changes were identified in the AMT gene that were absent from controls. We also identified a splice acceptor site mutation and five different non-synonymous variants in GLDC, which were found to significantly impair enzymatic activity and represent putative causative mutations. In order to functionally test the requirement for GCS activity in neural tube closure, we generated mice that lack GCS activity, through mutation of AMT. Homozygous Amt(-/-) mice developed NTDs at high frequency. Although these NTDs were not preventable by supplemental folic acid, there was a partial rescue by methionine. Overall, our findings suggest that loss-of-function mutations in GCS genes predispose to NTDs in mice and humans. These data highlight the importance of adequate function of mitochondrial folate metabolism in neural tube closure.
Links	PubMed PMC3298276 Online version:10.1093/hmg/ddr585
Keywords	Aminomethyltransferase/genetics; Animals; Glycine Decarboxylase Complex/metabolism; Glycine Decarboxylase Complex H-Protein/genetics; Glycine Dehydrogenase (Decarboxylating)/genetics; Humans; Mice; Mice, Knockout; Mutation; Mutation, Missense; Neural Tube Defects/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:GCST		GO:0019464:	ECO:0000315:				Figure 4: Mice that were heterozygous for the AMT- mutation had significantly decreased glycine cleavage system activity than wild type mice. Mice that were homozygous for the AMT- mutation had undetectable levels of GCS activity.	complete CACAO 9881

References

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