In other species: dog , pig , mule

Categories: Muscle phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 611556 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

Cross-species summary: Disintegration of muscle fibres, with consequent excretion of myoglobin in the urine.

Species-specific name: Equine rhabdomyolysis syndrome; Polysaccharide storage myopathy; Tying-up

Species-specific symbol: PSSM1

Species-specific description: Valber et al. (1996) identified a polysaccharide storage myopathy (a glycogen storage disorder) associated with exertional rhabdomyolysis in Quarter-horse related breeds.

History: Horses with clinical signs similar to this disorder were first reported by Carlstrom (1932). The disorder was first recognised as a skeletal muscle glycogenosis by Valberg et al. (1992).

Inheritance: The disorder is definitely familial, and there are suggestions of autosomal recessive inheritance. However, the published data are inconclusive on this point (Valberg et al., 1996). Dranchak et al. (2005) performed a segregation analysis that excluded all forms of single-locus inheritance other than autosomal dominant.

Mapping: By conducting a genome scan on 48 related affected and 48 unrelated normal Quarter Horses, each genotyped with 105 microsatellites spread across all chromosomes, McCue et al. (2008) mapped this disorder to the vicinity of microsatellite NVEQ018 on chromosome ECA10p. Genotyping the same and additional horses with additional ECA10p microsatellites narrowed the location corresponding to a 3 Mb region of human chromosome HSA19 from 51.9 Mb to 54.6 Mb.

Molecular basis: Noting that the only functional comparative gene in the candidate region of HSA19 was GYS1, McCue et al. (2008) sequenced this gene in a likely homozygous affected horse and a control horse, discovering a missense mutation (c.?G>A; p.Arg309His) whose segregation in other affected and normal horses was consistent with causality. Interestingly, McCue et al. (2008) presented evidence that this is a gain-of-function mutation: "it is more likely that the glycogen accumulation in PSSM horse muscle is due to the Arg309His mutation and results from enhanced activity and/or poor regulation of the mutant enzyme".

Clinical features: As summarised by McCue et al. (2008): "The phenotypic expression of PSSM ranges from muscle atrophy and progressive weakness in Draft horse breeds to muscle soreness and gait abnormalities in Warmblood breeds, and acute exertional rhabdomyolysis in Quarter Horses. The severity of clinical signs in PSSM ranges from muscle cramping and stretching out . . . to severe muscle pain and myoglobinuria and occasionally the complete inability to rise".

Pathology: Widespread presence of subsarcolemmal vacuoles and PAS-positive inclusions (Valberg et al., 1996).

Prevalence: As reported by McCue et al. (2008), "The His309 allele was found in either heterozygous or homozygous form in 356 horses from 15 different breeds including Quarter Horses, Paint horses, Appaloosa horses, 5 Draft horse breeds, 3 Warmblood breeds, the Morgan, Mustang, Rocky Mountain Horse breeds, as well as mixed breed horses and Warmblood horses of unspecified breed." Its frequency ranged "from 0.035 to 0.350 in different breeds". The presence of this allele in so many breeds suggests ancient origins. McCue et al. (2008) estimated its mean age at 159 generations, which means that "this mutation likely originated between 1200 to 1500 years ago . . . , prior to the separation of the modern breeds known today". McCoy et al. (2013) reported evidence that the 309His "mutation underwent historical selection in the Belgian [because "Under historical conditions of daily work and limited feed, excess muscle glycogen may have been advantageous"], but not in the Quarter Horse".

Breeds: American Paint (Horse) (VBO_0000897), Belgian Draft (Horse) (VBO_0000915), Haflinger (Horse) (VBO_0000978), Noric (Horse) (VBO_0001030), Quarter Horse (Horse) (VBO_0001057).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: