1Biol. Psychiatry 2011 Oct 70: 626-35
TitleLoss of function studies in mice and genetic association link receptor protein tyrosine phosphatase ? to schizophrenia.
AbstractSolid evidence links schizophrenia (SZ) susceptibility to neurodevelopmental processes involving tyrosine phosphorylation-mediated signaling. Mouse studies implicate the PTPRA gene, encoding protein tyrosine phosphatase RPTP?, in the control of radial neuronal migration, cortical cytoarchitecture, and oligodendrocyte differentiation. The human gene encoding RPTP?, PTPRA, maps to a chromosomal region (20p13) associated with susceptibility to psychotic illness.
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).
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.
The implication of this well-studied signaling protein in SZ risk and endophenotype manifestation provides novel entry points into the etiopathology of this disease.
SCZ Keywordsschizophrenia
2PLoS ONE 2014 -1 9: e112531
TitleResequencing and association analysis of PTPRA, a possible susceptibility gene for schizophrenia and autism spectrum disorders.
AbstractThe PTPRA gene, which encodes the protein RPTP-?, is critical to neurodevelopment. Previous linkage studies, genome-wide association studies, controlled expression analyses and animal models support an association with both schizophrenia and autism spectrum disorders, both of which share a substantial portion of genetic risks.
We sequenced the protein-encoding areas of the PTPRA gene for single nucleotide polymorphisms or small insertions/deletions (InDel) in 382 schizophrenia patients. To validate their association with the disorders, rare (minor allele frequency <1%), missense mutations as well as one InDel in the 3'UTR region were then genotyped in another independent sample set comprising 944 schizophrenia patients, 336 autism spectrum disorders patients, and 912 healthy controls.
Eight rare mutations, including 3 novel variants, were identified during the mutation-screening phase. In the following association analysis, L59P, one of the two missense mutations, was only observed among patients of schizophrenia. Additionally, a novel duplication in the 3'UTR region, 174620_174623dupTGAT, was predicted to be located within a Musashi Binding Element.
No evidence was seen for the association of rare, missense mutations in the PTPRA gene with schizophrenia or autism spectrum disorders; however, we did find some rare variants with possibly damaging effects that may increase the susceptibility of carriers to the disorders.
SCZ Keywordsschizophrenia