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  • 1
    Keywords: FOLLOW-UP ; COMPLEX ; COMPLEXES ; ASSOCIATION ; chromosome ; GENOMEWIDE SCREEN ; GENOMIC SCREEN ; LINKAGE ; SUSCEPTIBILITY ; LINKAGE ANALYSIS ; genetics ; REGION ; REGIONS ; PERVASIVE DEVELOPMENTAL DISORDERS ; CHROMOSOMES ; development ; SCREEN ; autism ; PREDISPOSITION ; IDENTITY ; COMPLEX TRAITS ; DIAGNOSTIC OBSERVATION SCHEDULE ; GENETIC-LINKAGE
    Abstract: Background and methods: Autism is a severe neurodevelopmental disorder, which has a complex genetic predisposition. The ratio of males to females affected by autism is approximately 4: 1, suggesting that sex specific factors are involved in its development. We reported previously the results of a genomewide screen for autism susceptibility loci in 83 affected sibling pairs ( ASP), and follow up analysis in 152 ASP. Here, we report analysis of an expanded sample of 219 ASP, using sex and parent of origin linkage modelling at loci on chromosomes 2, 7, 9, 15, and 16. Results: The results suggest that linkage to chromosomes 7q and 16p is contributed largely by the male male ASP (MLS = 2.55 v 0.12, and MLS = 2.48 v 0.00, for the 145 male - male and 74 male - female/ female - female ASP on chromosomes 7 and 16 respectively). Conversely linkage to chromosome 15q appears to be attributable to the male - female/ female - female ASP ( MLS = 2.62 v 0.00, for non-male and male - male ASP respectively). On chromosomes 2 and 9, all ASP contribute to linkage. These data, supported by permutation, suggest a possible sex limited effect of susceptibility loci on chromosomes 7, 15, and 16. Parent of origin linkage modelling indicates two distinct regions of paternal and maternal identity by descent sharing on chromosome 7 ( paternal MLS = 1.46 at similar to112 cM, and maternal MLS = 1.83 at similar to135 cM; corresponding maternal and paternal MLS = 0.53 and 0.28 respectively), and maternal specific sharing on chromosome 9 ( maternal MLS = 1.99 at,30 cM; paternal MLS = 0.02). Conclusion: These data support the possibility of two discrete loci underlying linkage of autism to chromosome 7, and implicate possible parent of origin specific effects in the aetiology of autism
    Type of Publication: Journal article published
    PubMed ID: 15689451
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  • 2
    Publication Date: 2018-09-21
    Description: SF3B1 , SRSF2 , and U2AF1 are the most frequently mutated splicing factor genes in the myelodysplastic syndromes (MDS). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Using RNA-seq, we determined the aberrantly spliced genes and dysregulated pathways in CD34 + cells of 84 patients with MDS. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. We identified aberrantly spliced events associated with clinical variables, and isoforms that independently predict survival in MDS and implicate dysregulation of focal adhesion and extracellular exosomes as drivers of poor survival. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. This study illuminates the effect of the common spliceosome mutations on the MDS phenotype and provides novel insights into disease pathophysiology.
    Keywords: Plenary Papers, Free Research Articles, Myeloid Neoplasia, CME article
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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