title: Zic2 hypomorphic mutant mice as a schizophrenia model and ZIC2 mutations identified in schizophrenia patients.
abstract: ZIC2 is a causal gene for holoprosencephaly and encodes a zinc-finger-type transcriptional regulator. We characterized Zic2(kd/+) mice with a moderate (40%) reduction in Zic2 expression. Zic2(kd/+) mice showed increased locomotor activity in novel environments, cognitive and sensorimotor gating dysfunctions, and social behavioral abnormalities. Zic2(kd/+) brain involved enlargement of the lateral ventricle, thinning of the cerebral cortex and corpus callosum, and decreased number of cholinergic neurons in the basal forebrain. Because these features are reminiscent of schizophrenia, we examined ZIC2 variant-carrying allele frequencies in schizophrenia patients and in controls in the Japanese population. Among three novel missense mutations in ZIC2, R409P was only found in schizophrenia patients, and was located in a strongly conserved position of the zinc finger domain. Mouse Zic2 with the corresponding mutation showed lowered transcription-activating capacity and had impaired target DNA-binding and co-factor-binding capacities. These results warrant further study of ZIC2 in the pathogenesis of schizophrenia.
authors.affiliation: Laboratory for Behavioral and Developmental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hatayama
authors.forename: Akira
authors.initials: A
authors.lastname: Ishiguro
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwayama
authors.forename: Noriko
authors.initials: N
authors.lastname: Takashima
authors.forename: Kazuto
authors.initials: K
authors.lastname: Sakoori
authors.forename: Tomoko
authors.initials: T
authors.lastname: Toyota
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Nozaki
authors.forename: Yuri S
authors.initials: YS
authors.lastname: Odaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yamada
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Jun
authors.initials: J
authors.lastname: Aruga
mesh_terms: D000328:Adult; D000818:Animals; D004195:Disease Models, Animal; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007564:Japan / Q000453:epidemiology; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D012307:Risk Factors; D012559:Schizophrenia / Q000453:epidemiology* / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human; C491811:Zic2 protein, mouse