Molecular bases of equine polysaccharide storage myopathies
2015-04
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Molecular bases of equine polysaccharide storage myopathies
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2015-04
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Polysaccharide Storage Myopathy (PSSM) is a form of glycogen storage disease in horses, characterized by abnormal polysaccharide inclusions in skeletal muscle. PSSM1 is caused by a dominant gain of function mutation in the GYS1 gene. PSSM1 horses can metabolize glycogen and have a normal flux of metabolites through glycolysis during maximal exercise, yet these horses demonstrate exercise intolerance, painful muscle cramping, and rhabdomyolysis during sub-maximal exercise. The link between excessive muscle glycogen, abnormal polysaccharide and rhabdomyolysis during sub-maximal exercise is less clear. To evaluate the changes in muscle that lead to this energy deficit, muscle gene expression profiles before and after a controlled exercise trial were evaluated in PSSM1 cases and controls by RNASeq. 201 genes were differentially expressed between cases and controls pre-trial, 301 genes were differently expressed between cases and controls pre-exercise (end of trial) and 803 genes were differentially expressed between cases and controls post-exercise (end of the trial). Gene set enrichment analysis revealed enrichment in pathways involving mitochondria biogenesis, oxidative phosphorylation, fatty acid metabolism, glycogen and glucose metabolism. DAVID was used to cluster the top differentially expressed genes based on their functional annotation. Clusters involved in inflammation were overrepresented. A second form of PSSM (PSSM2) has also been described. The mutation responsible for PSSM2 is unknown. Genome wide association data revealed significant markers associated with PSSM2 on equine chromosome 18 but no variants associated with PSSM2 were identified after extensive investigation of this region using a combination of target and whole genome sequencing in cases and controls. Imputation was then performed to increase the number of SNP markers in the initial GWA from 54,000 to close to 1.8 million markers, revealing new regions associated with PSSM2 on chromosomes 27 and 11. Haplotype analysis supported the association only on chromosome 11. The region of ECA11 encompasses several annotated genes. Next generation sequencing data from cases and controls revealed non-synonymous mutations in the phosphoribosylformylglycinamidine synthase gene in 2 out of 3 cases and none of the controls, identifying a new region in which to focus our efforts to define the genetic basis for PSSM2.
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University of Minnesota Ph.D. dissertation. April 2015. Major: Veterinary Medicine. Advisors: Molly McCue, James Mickelson. 1 computer file (PDF); vi, 201 pages.
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Teixeira, Raffaella. (2015). Molecular bases of equine polysaccharide storage myopathies. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/173808.
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