Systematic search for mutations in the human tissue inhibitor of metalloproteinases-3 (TIMP-3) gene on chromosome 22 and association study with schizophrenia

Several linkage studies have suggested that chromosome 22q12-q13 is a putat ive region for schizophrenic genes, In this study, the human tissue inhibit or of metalloproteinase-3 (TIMP-3) gene was investigated as positional cand idate gene for schizophrenia because of its regulatory function on extracel lular matrix proteins, cell adhesion molecules, and neural cell adhesion mo lecules in the brain, We systematically searched for the nucleotide variant s by sequencing all the exons and their flanking intronic sequences in a sa mple of Chinese schizophrenic patients from Taiwan, Two silent mutations in the exon 3 were identified: c.249T -->C at codon 83 (His) and c.261C -->T at codon 87 (Ser), However, no mutations causing amino acid alteration or a berrant splicing of transcripts were observed, Hence, it is unlikely that t he TLMP-3 gene itself may play an important role in the genetic susceptibil ity to schizophrenia, Further case control association study revealed a sig nificant difference of genotype distribution of the c.249T -->C between sch izophrenic patients and control, This finding supports that 22q12 is a schi zophrenia susceptible region, and it is likely that there might be other ge netic mutations in the neighborhood of the TIMP-3 gene locus that mag contr ibute to the susceptibility of schizophrenia. (C) 2001 Wiley-Liss, Inc.