Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans
| Autor: | Akira Hata, Nicholas D. E. Greene, Atsuo Kikuchi, Shigeo Kure, Caroline L Relton, Kazuko Fujiwara, Kit Yi Leung, Shoko Komatsuzaki, James Grinham, Yoichi Matsubara, Alexis A Robinson, Teiji Tominaga, Darren Partridge, Ayumi Narisawa, Andrew J. Copp, Philip Stanier, Yoichi Suzuki, Victoria Stone, Tetsuya Niihori, Peter Gustavsson, Mitsuyo Tanemura, Yoko Aoki |
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| Rok vydání: | 2011 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Candidate gene Mutation Missense Biology medicine.disease_cause Glycine Decarboxylase Complex H-Protein GCSH Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Aminomethyltransferase Animals Humans Missense mutation Neural Tube Defects Molecular Biology Gene Genetics (clinical) 030304 developmental biology Glycine Decarboxylase Complex Mice Knockout 0303 health sciences Mutation Glycine cleavage system Neural tube Articles General Medicine Glycine Dehydrogenase (Decarboxylating) medicine.anatomical_structure 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddr585 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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