Structure and polymorphisms of the human metabotropic glutamate receptor type 2 gene (GRM2): analysis of association with schizophrenia.

Abstract

Metabotropic glutamate receptors (mGluRs) belong to the class of GTP-binding protein coupled receptors and consist of eight different subtypes. The subtype 2 metabotropic glutamate receptor (mGluR2) gene (GRM2) is one of the possible candidate genes for schizophrenia. Phencyclidine (PCP)-induced increase in glutamate efflux and schizophrenia-like behavioral abnormalities were reduced by pretreatment of the mGluRII agonist LY354740 in rats and its effects are mediated via mGluR2. To evaluate involvement of the mGluR2 gene in the pathogenesis of schizophrenia, we isolated the human mGluR2 gene and determined the transcription initiation site, the entire nucleotide sequence and the chromosomal localization. The hmGluR2 gene spans 13 kb with six exons, including one non-coding exon. The gene was mapped to chromosome 3 p12-p11 by Radiation Hybrid Panel analysis. We screened polymorphisms in the coding exons of the mGluR2 gene, using the SSCP procedure. The thirteen polymorphisms identified included ten missense, one silent mutation and two one-base substitutions in the 5'-untranslated region. We genotyped 213 Japanese schizophrenics and 220 controls to study the association of polymorphisms in the mGluR2 gene with schizophrenia. As we found no statistically significant differences in allele frequencies of each polymorphism, these polymorphisms apparently do not play a major role in schizophrenia.