Epidemiological and genetic study of exertional rhabdomyolysis in a Warmblood horse family in Switzerland

Johlig, L.; Valberg, Stephanie J.; Mickelson, James R.; Klukowska, J.; Reusser, H. R.; Straub, R.; Gerber, Vinzenz

doi:10.1111/j.2042-3306.2010.00161.x

Cited by 17 publications

(16 citation statements)

References 29 publications

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“…Here, we employed a multi-disciplinary approach in order to determine if the basis for the previously-identified, increased GS activity in PSSM1-affected muscle [8] is associated with altered GS enzyme expression, dysregulation of GS activity, or a GS protein conformational change with possible constitutive activation. Our results reveal that the R309H mutation, responsible for this highly prevalent equine polyglucosan myopathy, present in over 20 breeds worldwide [12-15], is caused by constitutive activation; furthermore, we propose the probable mechanism, based on modelling analyses of the mutant GS structure.…”

Section: Discussionmentioning

confidence: 76%

“…This glycine is located at a turn at the C-terminal end of the helix containing R298 (equivalent to equine R309) and G6P binding contacts. It is therefore positioned to function as a typical glycine-hinge residue and the reported mutation-associated change in enzyme activity [15], provides further evidence that structural deviations in this region produce constitutive activation.…”

Section: Discussionmentioning

confidence: 99%

“…The R309H mutation is associated with increased GS activity in muscle from affected horses [8]. The identical mutation has now been reported in many horse breeds worldwide [12-15] suggesting dissemination from a single founder and in certain breeds, positive selection [16] perhaps due to the increased muscle glycogen storage in affected animals [8]. Since the ratio of GS: GBE activity is important in the formation of glycogen with a normal structure [17], filamentous alpha crystalline polysaccharide that forms in PSSM1-affected muscle likely develops because of an increased GS: GBE activity ratio [18] as seen in transgenic mice with constitutively active muscle GS [19].…”

Section: Introductionmentioning

confidence: 99%

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A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Maile

Hingst

Mahalingan

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Summary BACKGROUND Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. RESULTS PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. CONCLUSIONS Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Maile

Hingst

Mahalingan

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Whilst many horses with PSSM1 are asymptomatic (Johlig et al . ; Naylor et al . ), exertional rhabdomyolysis is the most commonly and perhaps easily recognised clinical syndrome.…”

Section: Clinical Presentationmentioning

confidence: 99%

Polysaccharide storage myopathy – the story so far

Naylor

2015

Equine Veterinary Education

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Summary Polysaccharide storage myopathy (PSSM) was first described in 1992 in Quarter Horses, Appaloosa and Paint‐related breeds with clinical signs of exertional rhabdomyolysis. The disease is characterised by the accumulation of excessive glycogen and diastase‐resistant amylopectin polysaccharide inclusions within skeletal muscle fibres. The discovery of a mutation in the glycogen synthase 1 (GYS1) gene in some, but not all, horses with the disease suggested that PSSM represents a group of diseases with similar pathology but different aetiologies and that the pathogenesis is more complex than initially thought. Type 1 PSSM (PSSM1) refers to horses with the GYS1 mutation and has subsequently been identified in a large number of breeds found in Europe and North America. Clinical presentations associated with PSSM1 can vary and increased muscle enzyme activity at rest or following exercise often accompanies PSSM1; however, such changes may not be present in all cases. A diagnosis of PSSM is made on the basis of histopathology or specifically PSSM1 is diagnosed by genotyping horses for the GYS1 mutation. Cases usually respond well to management changes, in particular a diet low in starch and high in fat when it is accompanied by regular exercise.

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“…; Johlig et al . ). Evidence therefore suggests that the GYS1 mutation is an important cause of PSSM in some breeds, and horses with the same specific mutation are regarded as having PSSM type 1 (McCue et al .…”

Section: Introductionmentioning

confidence: 97%

Nutritional considerations for equine rhabdomyolysis syndrome

Harris¹,

Rivero

2015

Equine Veterinary Education

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Summary Exertional rhabdomyolysis represents a syndrome of typically recurrent exercise‐associated muscle damage in horses that arises from a variety of aetiologies. Major advances have been made in recent years in our understanding of the pathophysiology of equine rhabdomyolysis syndrome (ERS), and a few specific causative genetic defects have been identified. Despite the fact that there is no single procedure or set of procedures (including diet and management) that can guarantee against further episodes of ERS, appropriate management of susceptible individuals, including nutrition, may help to reduce the likelihood, severity or frequency of future episodes. Whilst the dietary advice can be more specific and targeted for those with a known intrinsic muscle problem, for all affected individuals, regardless of the underlying cause, a balanced diet (which is suitable for the individual), together with a well‐designed exercise programme, should be the initial management target. This paper will briefly review the condition and give general nutrition and management advice.

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Epidemiological and genetic study of exertional rhabdomyolysis in a Warmblood horse family in Switzerland

Cited by 17 publications

References 29 publications

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Polysaccharide storage myopathy – the story so far

Nutritional considerations for equine rhabdomyolysis syndrome

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