An E321G MYH1 mutation is strongly associated with nonexertional rhabdomyolysis in Quarter Horses

Abstract

BackgroundAn E321G mutation in MYH1 was recently identified in Quarter Horses (QH) with immune‐mediated myositis (IMM) defined by a phenotype of gross muscle atrophy and myofiber lymphocytic infiltrates.Hypothesis/ObjectivesWe hypothesized that the MYH1 mutation also was associated with a phenotype of nonexertional rhabdomyolysis. The objective of this study was to determine the prevalence of the MYH1 mutation in QH with exertional (ER) and nonexertional (nonER) rhabdomyolysis.AnimalsQuarter Horses: 72 healthy controls, 85 ER‐no atrophy, 56 ER‐atrophy, 167 nonER horses selected regardless of muscle atrophy.MethodsClinical and histopathologic information and DNA was obtained from a database for (1) ER > 2 years of age, with or without atrophy and (2) nonER creatine kinase (CK) ≥ 5000 U/L, <5 years of age. Horses were genotyped for E321G MYH1 by pyrosequencing.ResultsThe MYH1 mutation was present in a similar proportion of ER‐no atrophy (1/56; 2%) and in a higher proportion of ER‐atrophy (25/85; 29%) versus controls (4/72; 5%). The MYH1 mutation was present in a significantly higher proportion of nonER (113/165; 68%) than controls either in the presence (39/42; 93%) or in absence (72/123; 59%) of gross atrophy. Lymphocytes were present in <18% of muscle samples with the MYH1 mutation.Conclusions and Clinical ImportanceAlthough not associated with ER, the MYH1 mutation is associated with atrophy after ER. The MYH1 mutation is highly associated with nonER regardless of whether muscle atrophy or lymphocytic infiltrates are present. Genetic testing will enhance the ability to diagnose MYH1 myopathies (MYHM) in QH.

Prevalence of the E321GMYH1variant for immune‐mediated myositis and nonexertional rhabdomyolysis in performance subgroups of American Quarter Horses

“…A missense E321G MYH1 mutation in the gene that encodes the MYH1 protein found in type IIX myofibers was found to be responsible for IMM as well as for a codominantly inherited form of severe acute non‐ER in QH‐related breeds . These 2 myopathies have been grouped under the heading of myosin heavy chain 1 myopathies (MYHM) based on this newly recognized etiology . The major finding in the present study was the relatively common occurrence of the E321G MYH1 mutation in QHs.…”

“…Immune‐mediated myositis in American QHs is characterized by autoimmunity directed at type IIX myofibers, resulting in episodes of marked muscle atrophy . A missense E321G MYH1 mutation in the gene that encodes the MYH1 protein found in type IIX myofibers was found to be responsible for IMM as well as for a codominantly inherited form of severe acute non‐ER in QH‐related breeds . These 2 myopathies have been grouped under the heading of myosin heavy chain 1 myopathies (MYHM) based on this newly recognized etiology .…”

“…In horses carrying this allele, exposure of the novel myosin isoform to the extracellular environment appears to initiate lymphocytic infiltration and destruction of predominantly type IIX myofibers . More recently, this same genetic variant was associated with nonexertional rhabdomyolysis (non‐ER) in QHs with or without atrophy and lymphocytic infiltrates …”

Ten years of the horse reference genome: insights into equine biology, domestication and population dynamics in the post‐genome era

“…A nonsense mutation in B3GALNT2 involved in muscular dystrophy with hydrocephalus in stillborn foals was discovered previously by the same group using similar techniques (Ducro et al 2015). This approach was also utilized to unravel the genetic mutation responsible for both immune-mediated myositis (Finno et al 2018) and non-exertional rhabdomyolysis (Valberg et al 2018) in the Quarter Horse as well as congenital hepatic fibrosis in the Swiss Franches-Montagnes (Drogemuller et al 2014).…”

Biallelic loss-of-function OBSCN variants predispose individuals to severe, recurrent rhabdomyolysis

“…9 Further, Alsaif et al have reported a single case of rhabdomyolysis associated with a homozygous missense variant in MYH1, the gene encoding myosin heavy chain 2X 10 , and a MYH1 missense variant is strongly associated with non-exertional rhabdomyolysis in Quarter horses. 11 In addition, variants in known muscular dystrophy genes can also predispose a patient to rhabdomyolysis; in some cases rhabdomyolysis can be the presenting symptom of an underlying muscular dystrophy, e.g. ANO5, CAV3 DMD, FKRP and SGCA 5; 6; 12-15 or neurogenerative disease, e.g.…”