title: Ablation of Mrds1/Ofcc1 induces hyper-γ-glutamyl transpeptidasemia without abnormal head development and schizophrenia-relevant behaviors in mice.
abstract: Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as "the Japan Mouse Clinic". No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia.
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan. tohnishi@brain.riken.jp
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ohnishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Yamada
authors.forename: Akiko
authors.initials: A
authors.lastname: Watanabe
authors.forename: Hisako
authors.initials: H
authors.lastname: Ohba
authors.forename: Toru
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Yota
authors.initials: Y
authors.lastname: Honma
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Motoko
authors.initials: M
authors.lastname: Maekawa
authors.forename: Kazutada
authors.initials: K
authors.lastname: Watanabe
authors.forename: Sevilla D
authors.initials: SD
authors.lastname: Detera-Wadleigh
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Wakana
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001522:Behavior, Animal; D019465:Craniofacial Abnormalities / Q000097:blood / Q000150:complications / Q000201:enzymology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D006257:Head; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000097:blood / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000097:blood*
chemical_list: C491851:OFCC1 protein, human; D011506:Proteins; D012333:RNA, Messenger; C546857:ojoplano protein, mouse; D005723:gamma-Glutamyltransferase