A missense mutation in MYH1 is associated with susceptibility to immune-mediated myositis in Quarter Horses.
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ABSTRACT:
SUBMITTER: Finno CJ
PROVIDER: S-EPMC5838957 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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Project description:Myosinopathies are defined as a group of muscle disorders characterized by mutations in genes encoding myosin heavy chains. Their exact molecular and cellular mechanisms remain unclear. In the present study, we have focused our attention on a MYH1-related E321G amino acid substitution within the head region of the type IIx skeletal myosin heavy chain, associated with clinical signs of atrophy, inflammation and/or profound rhabdomyolysis, known as equine myosin heavy chain myopathy. We performed Mant-ATP chase experiments together with force measurements on isolated IIx myofibres from control horses (MYH1E321G-/-) and Quarter Horses homozygous (MYH1E321G+/+) or heterozygous (MYH1E321G+/-) for the E321G mutation. The single residue replacement did not affect the relaxed conformations of myosin molecules. Nevertheless, it significantly increased its active behaviour as proven by the higher maximal force production and Ca2+ sensitivity for MYH1E321G+/+ in comparison with MYH1E321G+/- and MYH1E321G-/- horses. Altogether, these findings indicate that, in the presence of the E321G mutation, a molecular and cellular hyper-contractile phenotype occurs which could contribute to the development of the myosin heavy chain myopathy.
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Project description:BackgroundThe prevalence of clinical signs and factors triggering muscle atrophy and rhabdomyolysis associated with an MYH1E321G mutation in Quarter Horses and related breeds (QH) remain poorly understood.Hypothesis/objectivesDetermine the prevalence and potential triggers of atrophy and stiffness in horses homozygous reference (N/N), heterozygous (My/N), and homozygous (My/My) for the MYH1E321G mutation.AnimalsTwo-hundred seventy-five N/N, 100 My/N, and 10 My/My QH.MethodsA retrospective case-control study using a closed-ended questionnaire completed by clients of the Veterinary Genetics Laboratory at the University of California, Davis. History of clinical signs, disease, vaccination and performance were analyzed by genotype using contingency testing.ResultsAtrophy occurred in proportionately more horses with MYH1E321G (My) than N/N QH and more frequently in My/My than My/N QH (P < .001; My/My 8/10 [80%], My/N 17/100 [17%], N/N 29/275 [11%]). More My/My horses had rapid atrophy (P < .001), with recurrence in 50%. Fewer My/My horses recovered versus My/N QH (P < .001). Stiffness was common across genotypes (P = .100; My/My 4/10 [40%], My/N 18/100 [18%], N/N 48/275 [17%]). Three months before the observed atrophy and stiffness, 47% of MYH1E321G QH were vaccinated or had respiratory or gastrointestinal disease. Horses achieving 100% expected performance did not differ across genotypes (50% My/My, 71% My/N, 55% N/N), but, only 4/10 My/My QH were competing. My/N horses achieved national or world championships or both.Conclusion and clinical importanceApproximately 20% of My/N QH develop rapid atrophy. Atrophy is more common (80%) in homozygous My/My QH and less likely to resolve. Inciting causes such as vaccination and infection are inapparent in over half of cases.
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Project description:Overtraining syndrome (OTS) is the reduction in performance due to excess training and lack of proper recovery, which can lead to a chronic deprivation of energy and reduction in the repair of damage that can accumulate over time. Here, the effect of acute, intense physical exercise on the expression of innate and adaptive immune genes in 12 racing-bred American Quarter Horses, after resting for 3 days and immediately after intense exercise for 1.8 miles were compared. The expression of 84 genes related to innate and adaptive immune responses was analyzed. Significant variation among individuals and between sexes was observed. The analysis showed that five genes were differentially expressed in both females and males, three only in females, and two in males. The upregulated genes were IL13 (male only), CCR4 (female only), TLR6, TLR9 (female only), NFKBIA, CXCR3, and TLR4, while the downregulated genes were IL6 (female only), CD4 (male only), and MYD88. The three main pathways containing genes that were affected by acute, intense physical exercise were Th1 and Th2 cell differentiation, and the NF-kappa B and chemokine signaling pathways, suggesting the activation of the proinflammatory responses as a result of the stress from the acute exercise. Gene expression could be used to assess indications of OTS.
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Project description:PurposeSchwannomatosis, a subtype of neurofibromatosis, is characterized by multiple benign, nonvestibular, nonintradermal schwannomas. Although the tumor suppressor SMARCB1 gene has been frequently identified as the underlying genetic cause of half of familial and ~10% of sporadic schwannomatosis, for most other cases, further causative genes remain to be discovered. Herein, we characterize the genome of a schwannomatosis family without constitutional inactivation of the SMARCB1 gene to explore novel genomic alterations predisposing individuals to the familial disease.MethodsWe performed whole-genome/exome sequencing on genomic DNA of both schwannomatosis-affected and normal members of the family.ResultsWe identified a novel missense mutation (p.Asp208His; c.622G>C) in the coenzyme Q10 (CoQ10) biosynthesis monooxygenase 6 gene (COQ6) in schwannomatosis-affected members. The deleterious effects of the COQ6 mutations were validated by their lack of complementation in a coq6-deficient yeast mutant. Our study further indicated that the resultant haploinsufficiency of COQ6 might lead to CoQ10 deficiency and chronic overproduction of reactive oxygen species in Schwann cells.ConclusionAlthough the exact oncogenetic mechanisms in this schwannomatosis family remain to be elucidated, our data strongly indicate a probable role of COQ6 mutation and CoQ10 deficiency in the development of familial schwannomatosis.Genet Med 16 10, 787-792.
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