Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature

Abstract

The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.

Calcium and Redox Liaison: A Key Role of Selenoprotein N in Skeletal Muscle

“…RYR1 triggers Ca 2+ efflux from this cellular compartment into the cytosol, leading to excitation–contraction coupling [ 9 , 10 ]. A lower percentage of the autosomal recessive forms of multi-minicore disease are due to mutations of the Selenoprotein N gene ( SEPN1/SELENON ) [ 1 , 11 ]. Different types of mutation are associated with SEPN1-related myopathy, including missense variants, small duplications/insertions, deletions, nonsense and splice mutations and also CNVs (Copy Number Variations) [ 12 , 13 , 14 ].…”

Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy

“…In this regard, the correlation of genetic findings together with clinical, histological, and muscle imaging data may be helpful. All these diseases show impaired intracellular calcium homeostasis through different pathomechanisms, such as leaky Ryr1 channels, reduced Ryr1 expression, impaired Ryr1 interdomain interactions, increased sensitivity to modulators/activators, or impaired excitation–contraction coupling [ 113 ]. The impaired calcium homeostasis may cause secondary cellular dysfunction with increased oxidative stress, abnormal post-translational modifications, mitochondrial dysfunction, and altered protein–protein and protein–ligand interactions [ 113 ].…”

Role of molecular and metabolic defects in impaired performance of dystrophic skeletal muscles

“…Since the SR is intimately involved in maintaining the intracellular Ca 2+ -homeostasis, different defects in this intercellular organelle have been identified in muscular dystrophy. Marked alterations in the structure and function of Ca 2+ -release channel or ryanodine receptor in the SR have been demonstrated in dystrophic muscle [235][236][237]. A progressive increase in the expression of ryanodine receptor and ryanodine receptor binding in the SR has been shown to occur during the development of muscular dystrophy [238].…”