Muscle relaxation is brought about by calcium reuptake into the SR by the sarco(endo)plasmic CaATPase (SERCA). Calcium release from the SR via the calcium release channel ryanodine receptor is initiated by a voltage-dependent orthograde signal delivered by the dihydropyridine receptor (DHPR), the voltage sensor localized in the transverse tubule membrane (T-tubules). Muscle contraction is brought about by a massive release of Ca 2+ from the sarcoplasmic reticulum (SR) throughout the entire length of the muscle fiber via a process called excitation-contraction coupling (ECC) ( 1, 2). In summary, bi-allelic expression of the RyR1 p.A4329D mutation phenotypically differs from mono-allelic expression of this mutation in a compound heterozygous carrier. In particular, the bi-allelic RyR1 p.A4329D mutation caused a milder phenotype than its mono-allelic expression, leading to changes in the biochemical properties and physiological function only of slow-twitch muscles and largely sparing fast-twitch muscles. Our results revealed that the expression of two alleles carrying the same mutation or of one allele with the mutation in combination with a hypomorphic allele does not result in functionally equal outcomes and impacts skeletal muscles differently. To study in more detail the biochemistry and pathophysiology of recessive RYR1 myopathies, here we investigated a mouse model we recently generated by analyzing the effect of bi-allelic versus mono-allelic expression of the RyR1 p.A4329D mutation. This should result in 50% reduced expression of the ryanodine receptor in skeletal muscle, but its observed content is even lower. Because of nonsense-mediated decay, most hypomorphic alleles are not expressed, resulting in homozygous expression of the missense mutation allele. Within the latter group, those carrying a hypomorphic mutation in one allele and a missense mutation in the other are the most severely affected. Mutations in the ryanodine receptor 1 ( RYR1) gene are associated with several human congenital myopathies, including the dominantly inherited central core disease and exercise-induced rhabdomyolysis, and the more severe recessive phenotypes, including multiminicore disease, centronuclear myopathy, and congenital fiber type disproportion.
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