The Center proposes four postulates for investigating the role of genetic polymorphism in the alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) in schizophrenia: (1) identification and association of polymorphisms in CHRNA7 with schizophrenia, (2) demonstration of a functional effect of the polymorphism expression at the cellular level, (3) relation of the polymorphisms to deficits in brain function associated with the illness, and (4) reversal of the deficits in brain function by treatment directed at the cellular dysfunction caused by CHRNA7. This Project will address Postulates 1 and 2 by providing for the Center Investigators, genotyping of DNA from both live subjects and from postmortem brain, and in vitro evaluation of association with diagnosis and with function. CHRNA7 has been selected as the most likely candidate gene in the chromosome 15q14 linkage region by multiple biological and genetic studies. Functional mutations, consistent with reduced expression of the gene, were found in the proximal promoter region of the CHRNA7 gene. These are associated with both schizophrenia and the P50 deficit in the disease. Additional regulatory regions have been found in the 5' upstream region of the gene that contain polymorphic sites. This Project, Aim 1 will complete genotyping in 5' upstream regulatory regions, sequence the remaining sections of the gene in 10 probands from linked pedigrees, and investigate an associated intronic variant that may affect RNA splicing. SNPs in the four other genes in this region will be examined as well. As suggested by the Reviewers, we will also provide SNP genotyping for another gene with functional mutations, COMT, for association with schizophrenia and the phenotypes being investigated in this and other projects. For Postulate 2, Aim 2 will investigate the association of CHRNA7 mutations with CHRNA7 mRNA and protein expression in human postmortem brain of control and schizophrenic subjects.
In Aim 3, we will further investigate the effects of CHRNA7 associated and functional mutations on the expression of other genes, utilizing microarray technology. The consequences of mutations in CHRNA7 on expression of CHRNA7, itself, and of other genes may have pathophysiological importance for the projects in the Center.
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