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Browsing by Author "Teixeira, Raffaella"

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    Molecular bases of equine polysaccharide storage myopathies
    (2015-04) Teixeira, Raffaella
    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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    Role of coat color genotypes in risk and severity of melanoma in gray Quarter Horses
    (2013-06) Teixeira, Raffaella
    Both graying and melanoma formation in horses have recently been linked to a duplication in the syntaxin-17 (STX17) gene. This duplication, as well as a mutation in the agouti signaling protein (ASIP) gene that increases melanocortin-1-receptor (MC1R) pathway signaling, affect melanoma risk and severity in gray horses. We hypothesized that melanoma susceptibility in gray Quarter Horses (QH) is lower than gray horses from other breeds, and that this might be due to decreased MC1R signaling resulting from a high incidence of the MC1R chestnut coat color allele in the QH population. Blood or hair root samples were collected from 335 gray QH with and without dermal melanomas, for DNA extraction and genotyping for STX17, ASIP and MC1R genes. Age, gender and external melanoma presence and grade were recorded. The effect of age and genotype on melanoma presence and severity was evaluated by candidate gene association study. The melanoma prevalence and grade in this QH cohort were lower than in other breeds. Age was significantly associated with melanoma prevalence and severity. No significant effect of MC1R genotype on melanoma prevalence or severity was identified. In contrast to prior reports, an effect of ASIP genotype on both melanoma prevalence and grade was not detected. Homozygosity of STX17 was low and precluded evaluation of the gray allele effect on melanoma presence and severity. Melanoma prevalence and severity appears to be lower in gray QH than in other breeds. This could be due to infrequent STX17 homozygosity, a mitigating effect of the MC1R mutation on ASIP potentiation of melanoma, other genes in the MC1R signaling pathway, or differences in breed genetic background.