title: Loss of function studies in mice and genetic association link receptor protein tyrosine phosphatase α to schizophrenia.
abstract: BACKGROUND
  Solid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the Ptpra gene, encoding protein tyrosine phosphatase RPTPα, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTPα, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.
  
  
  METHODS
  We characterized neurobehavioral parameters, as well as gene expression in the central nervous system, of mice with a null mutation in the Ptpra gene. We searched for genetic association between polymorphisms in PTPRA and schizophrenia risk (two independent cohorts, 1420 cases and 1377 controls), and we monitored PTPRA expression in prefrontal dorsolateral cortex of SZ patients (35 cases, 2 control groups of 35 cases).
  
  
  RESULTS
  We found that Ptpra⁻/⁻ mice reproduce neurobehavioral endophenotypes of human SZ: sensitization to methamphetamine-induced hyperactivity, defective sensorimotor gating, and defective habituation to a startle response. Ptpra loss of function also leads to reduced expression of multiple myelination genes, mimicking the hypomyelination-associated changes in gene expression observed in postmortem patient brains. We further report that a polymorphism at the PTPRA locus is genetically associated with SZ, and that PTPRA mRNA levels are reduced in postmortem dorsolateral prefrontal cortex of subjects with SZ.
  
  
  CONCLUSIONS
  The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.
authors.affiliation: Conte Center for the Neuroscience of Mental Disorders, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Nagahide
authors.initials: N
authors.lastname: Takahashi
authors.forename: Karin Sandager
authors.initials: KS
authors.lastname: Nielsen
authors.forename: Branko
authors.initials: B
authors.lastname: Aleksic
authors.forename: Steffen
authors.initials: S
authors.lastname: Petersen
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Itaru
authors.initials: I
authors.lastname: Kushima
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vacaresse
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
authors.forename: Véronique
authors.initials: V
authors.lastname: Dubreuil
authors.forename: Naheed
authors.initials: N
authors.lastname: Mirza
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics; D011110:Polymorphism, Genetic; D017397:Prefrontal Cortex / Q000378:metabolism; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D012565:Schizophrenic Psychology
chemical_list: C516841:PTPRA protein, human; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4