title: Mutations in genes encoding the glycine cleavage system predispose to neural tube defects in mice and humans.
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.
authors.affiliation: Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Narisawa
authors.forename: Shoko
authors.initials: S
authors.lastname: Komatsuzaki
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Kazuko
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Tanemura
authors.forename: Akira
authors.initials: A
authors.lastname: Hata
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
authors.forename: James
authors.initials: J
authors.lastname: Grinham
authors.forename: Kit-Yi
authors.initials: KY
authors.lastname: Leung
authors.forename: Darren
authors.initials: D
authors.lastname: Partridge
authors.forename: Alexis
authors.initials: A
authors.lastname: Robinson
authors.forename: Victoria
authors.initials: V
authors.lastname: Stone
authors.forename: Peter
authors.initials: P
authors.lastname: Gustavsson
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Copp
authors.forename: Nicholas D E
authors.initials: ND
authors.lastname: Greene
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
mesh_terms: D050960:Aminomethyltransferase / Q000235:genetics*; D000818:Animals; D050959:Glycine Decarboxylase Complex / Q000378:metabolism; D050961:Glycine Decarboxylase Complex H-Protein / Q000235:genetics*; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000235:genetics*
chemical_list: D050961:Glycine Decarboxylase Complex H-Protein; D050959:Glycine Decarboxylase Complex; D050841:Glycine Dehydrogenase (Decarboxylating); D050960:Aminomethyltransferase