Epidemiological studies have highlighted the strong influence of genetic susceptibility on schizophrenia (SZ). Although numerous studies have mapped SZ loci, the number of replicated associations remains scarce. Moreover, causative alleles remain elusive, in part due to genetic and allelic heterogeneity. Together with our colleagues, we have shown that members of the pericentriolar matrix contribute loss of function alleles to the pathogenesis of SZ. We have focused on PCM1, a protein which we have shown to bind to DISC1 and to harbor loss of function mutations in SZ patients. We have modeled this lesion in the mouse;our preliminary data suggest that loss of PCM1 causes anatomical and behavioral defects, some of which present in heterozygotes. Furthermore, we have found that not only PCM1 but also centrosomal proteins interact preferentially with phosphorylated DISC1 to mediate a switch from proliferation to migration during early corticogenesis. Based on these data we propose to extend our studies and understand a) how loss of PCM1 affects cortical architecture and behavior;b) whether loss of this protein (and concomitant centrosomal disorganization) exhibits progressive phenotypes. Second, we will examine a new protein, RPGRIP1L, which we showed to interact with both PCM1 and phospho-DISC1, and which has been identified at genome-wide significance to be associated with SZ. We will sequence this transcript in 384 SZ cases and 384 controls, functionally test all resultant alleles using our now established zebrafish complementation assay and ask whether coding RPGRIP1L changes contribute to SZ. Finally, we will extend our studies to novel pericentriolar proteins. Specifically, we will parse 49 positional SZ candidates loci that encode centrosomal proteins and identify transcripts for which a) loss of function phenocopies the biochemical Wnt defect of PCM1 and DISC1 loss of function;and b) preferentially bind to phosphorylated DISC1. These will then be tested in our genetic cohort for candidate susceptibility alleles. These studies, together with the other Center groups, will enhance our understanding of SZ and will provide both new genetic markers and potential therapeutic pathways.
Schizophrenia is a common disorder that represents a significant socioeconomic burden. Project 2, as part of this Conte Center, will bring to bear a synthesis of genetic, model organisms, and biochemistry to identify novel SZ genes as they pertain to neurodevelopment and develop tools that will be able to test the functional significance of candidate mutations found in SZ patients.
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