Cytosolic protein interactions of the schizophrenia susceptibility gene dysbindin.

Using immunoprecipitation, mass spectrometry, and western blot analysis we investigated cytosolic protein interactions of the schizophrenia susceptibility gene dysbindin in mammalian cells. We identified novel interactions with members of the exocyst, dynactin and chaperonin containing T-complex protein complexes, and we confirmed interactions reported previously with all members of the biogenesis of lysosome-related organelles complex-1 and the adaptor-related protein complex 3. We report interactions between dysbindin and the exocyst and dynactin complex that confirm a link between two important schizophrenia susceptibility genes: dysbindin and disrupted-in-schizophrenia-1. To expand upon this network of interacting proteins we also investigated protein interactions for members of the exocyst and dynactin complexes in mammalian cells. Our results are consistent with the notion that impairment of aspects of the synaptic vesicle life cycle may be a pathogenic mechanism in schizophrenia.

CAG-encoded polyglutamine length polymorphism in the human genome.

BACKGROUND: Expansion of polyglutamine-encoding CAG trinucleotide repeats has been identified as the pathogenic mutation in nine different genes associated with neurodegenerative disorders. The majority of individuals clinically diagnosed with spinocerebellar ataxia do not have mutations within known disease genes, and it is likely that additional ataxias or Huntington disease-like disorders will be found to be caused by this common mutational mechanism. We set out to determine the length distributions of CAG-polyglutamine tracts for the entire human genome in a set of healthy individuals in order to characterize the nature of polyglutamine repeat length variation across the human genome, to establish the background against which pathogenic repeat expansions can be detected, and to prioritize candidate genes for repeat expansion disorders. RESULTS: We found that repeats, including those in known disease genes, have unique distributions of glutamine tract lengths, as measured by fragment analysis of PCR-amplified repeat regions. This emphasizes the need to characterize each distribution and avoid making generalizations between loci. The best predictors of known disease genes were occurrence of a long CAG-tract uninterrupted by CAA codons in their reference genome sequence, and high glutamine tract length variance in the normal population. We used these parameters to identify eight priority candidate genes for polyglutamine expansion disorders. Twelve CAG-polyglutamine repeats were invariant and these can likely be excluded as candidates. We outline some confusion in the literature about this type of data, difficulties in comparing such data between publications, and its application to studies of disease prevalence in different populations. Analysis of Gene Ontology-based functions of CAG-polyglutamine-containing genes provided a visual framework for interpretation of these genes' functions. All nine known disease genes were involved in DNA-dependent regulation of transcription or in neurogenesis, as were all of the well-characterized priority candidate genes. CONCLUSION: This publication makes freely available the normal distributions of CAG-polyglutamine repeats in the human genome. Using these background distributions, against which pathogenic expansions can be identified, we have begun screening for mutations in individuals clinically diagnosed with novel forms of spinocerebellar ataxia or Huntington disease-like disorders who do not have identified mutations within the known disease-associated genes.

Satellog: a database for the identification and prioritization of satellite repeats in disease association studies.

BACKGROUND: To date, 35 human diseases, some of which also exhibit anticipation, have been associated with unstable repeats. Anticipation has been reported in a number of diseases in which repeat expansion may have a role in etiology. Despite the growing importance of unstable repeats in disease, currently no resource exists for the prioritization of repeats. Here we present Satellog, a database that catalogs all pure 1-16 repeat unit satellite repeats in the human genome along with supplementary data. Satellog analyzes each pure repeat in UniGene clusters for evidence of repeat polymorphism. RESULTS: A total of 5,546 such repeats were identified, providing the first indication of many novel polymorphic sites in the genome. Overall, polymorphic repeats were over-represented within 3'-UTR sequence relative to 5'-UTR and coding sequence. Interestingly, we observed that repeat polymorphism within coding sequence is restricted to trinucleotide repeats whereas UTR sequence tolerated a wider range of repeat period polymorphisms. For each pure repeat we also calculate its repeat length percentile rank, its location either within or adjacent to EnsEMBL genes, and its expression profile in normal tissues according to the GeneNote database. CONCLUSION: Satellog provides the ability to dynamically prioritize repeats based on any of their characteristics (i.e. repeat unit, class, period, length, repeat length percentile rank, genomic co-ordinates), polymorphism profile within UniGene, proximity to or presence within gene regions (i.e. cds, UTR, 15 kb upstream etc.), metadata of the genes they are detected within and gene expression profiles within normal human tissues. Unstable repeats associated with 31 diseases were analyzed in Satellog to evaluate their common repeat properties. The utility of Satellog was highlighted by prioritizing repeats for Huntington's disease and schizophrenia. Satellog is available online at http://satellog.bcgsc.ca.