Journal Article

Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans

Ayumi Narisawa, Shoko Komatsuzaki, Atsuo Kikuchi, Tetsuya Niihori, Yoko Aoki, Kazuko Fujiwara, Mitsuyo Tanemura, Akira Hata, Yoichi Suzuki, Caroline L. Relton, James Grinham, Kit-Yi Leung, Darren Partridge, Alexis Robinson, Victoria Stone, Peter Gustavsson, Philip Stanier, Andrew J. Copp, Nicholas D.E. Greene, Teiji Tominaga, Yoichi Matsubara and Shigeo Kure

in Human Molecular Genetics

Volume 21, issue 7, pages 1496-1503
Published in print April 2012 | ISSN: 0964-6906
Published online December 2011 | e-ISSN: 1460-2083 | DOI:

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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.

Journal Article.  4831 words.  Illustrated.

Subjects: Genetics and Genomics

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