Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels

Backround: We previously reported a reduction in serum levels of D-Serine, an endogenons co-agonist of the N-methyl-D-aspartate (NMDA) receptor, in schizophrenia, supporting The hypofunction hypothesis is of NMDA neurotransmission in schizophrenia. In this study, we examined the genetic roles of serine racemase (SRR), an enzyme catalyzing the formation of D-serine from L-serine, and D-amino-acid oxidase (DAO) in the susceptibility to schizophrenia and the regulation of serum D-serine levels. Methods: We determined the complete cDNA and genomic structures of SRR? and performed mutation screening. Single nucleotide polymorphisms (SNP) in SRR and DAO were tested for their association with schizophrenia in both case-control control and family-based designs and for correlation with serum levels of D-serine. Results. Genomic analyses revealed that human brain SRR transcripts consist of four isoforms with one major species, which were derived from alternative use of various 5 end exons. Genetic association analysis showed no significant association between SRR/DAO and schizophrenia. We replicated the decreased serum D-Serine levels in schizophrenia in the sample set, but D-Serine levels did not correlate with SRR/DAO genotypes. Conclusions: The SRR/DAO are not likely to be major genetic determinants in the development of schizophrenia or control of serum D-serine levels.