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 putative region for schizophrenic genes. In this study, the human tissue inhibitor of metalloproteinase-3 (TIMP-3) gene was investigated as positional candidate gene for schizophrenia because of its regulatory function on extracellular matrix proteins, cell adhesion molecules, and neural cell adhesion molecules in the brain. We systematically searched for the nucleotide variants by sequencing all the exons and their flanking intronic sequences in a sample 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 aberrant splicing of transcripts were observed. Hence, it is unlikely that the TIMP-3 gene itself may play an important role in the genetic susceptibility to schizophrenia. Further case control association study revealed a significant difference of genotype distribution of the c.249T→C between schizophrenic patients and control. This finding supports that 22q12 is a schizophrenia susceptible region, and it is likely that there might be other genetic mutations in the neighborhood of the TIMP-3 gene locus that may contribute to the susceptibility of schizophrenia.