Recessive mutations in RYR1 are a common cause of congenital fiber type disproportion

Clarke, Nigel F.; Waddell, Leigh B.; Cooper, Sandra T.; Perry, Margaret M.; Smith, Robert L.; Kornberg, Andrew J.; Muntoni, F.; Lillis, Suzanne; Straub, Volker; Bushby, Kate; Guglieri, Michela; King, Mary D.; Farrell, Michael; Marty, Isabelle; Lunardi, Joël; Monnier, Nicole; North, Klaus

doi:10.1002/humu.21278

Cited by 156 publications

(128 citation statements)

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“…While MHS (discussed above) is also caused by mutations in RYR1, the term RYR1-related myopathies generally refers to disorders associated with persistent/chronic muscle dysfunction. These include several subtypes of congenital myopathy: central core disease [21], multiminicore myopathy [22], centronuclear myopathy (CNM) [23], congenital fiber-type disproportion [24], and core-rod myopathy (Fig. 2).…”

Section: Ryr1-related Myopathiesmentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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The triad is a skeletal muscle substructure responsible for the regulation of excitation-contraction coupling. It is formed by the close apposition of the T-tubule and the terminal sarcoplasmic reticulum. A rapidly growing list of skeletal myopathies, here referred to as triadopathies, are caused by gene mutations in components of the triad. These disorders, at their root, are caused by defects in excitation contraction coupling and intracellular calcium homeostasis. Secondary abnormalities in triad structure and/or function are also reported in several muscle diseases, most notably certain muscular dystrophies. This review highlights the current understanding of both primary and secondary triadopathies, and identifies important concepts yet to be fully addressed in the field. The emphasis of the review is both on the pathogenesis of triadopathies and their potential treatment.

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Section: Ryr1-related Myopathiesmentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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“…recessive RYR1 mutations no dysregulation of Ca 2+ homeostasis was detected [55]. This result is puzzling since muscle biopsies from the same patients show significant depletion of RyR1 protein, which should lead to a pronounced reduction of the amount of Ca 2+ released following RyR1 activation [55][56][57]. In a recent study we addressed the pathophysiology of recessive RYR1 mutations and in particular the epigenetic mechanism(s) responsible for bringing about such a drastic decrease of RyR1 protein in the muscles of patients [55].…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives

Treves

Jungbluth

Voermans

et al. 2017

Seminars in Cell & Developmental Biology

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a b s t r a c tThe physiological process by which Ca 2+ is released from the sarcoplasmic reticulum is called excitationcontraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca 2+ channel localized on the transverse tubules. Voltage-induced conformational changes in the dihydropyridine receptor activate the ryanodine receptor Ca 2+ release channel of the sarcoplasmic reticulum. The released Ca 2+ binds to troponin C, enabling contractile thick-thin filament interactions. The Ca 2+ is subsequently transported back into the sarcoplasmic reticulum by specialized Ca 2+ pumps (SERCA), preparing the muscle for a new cycle of contraction. Although other proteins are involved in excitation-contraction coupling, the mechanism described above emphasizes the unique role played by the two Ca 2+ channels (the dihydropyridine receptor and the ryanodine receptor), the SERCA Ca 2+ pumps and the exquisite spatial organization of the membrane compartments endowed with the proteins responsible for this mechanism to function rapidly and efficiently. Research over the past two decades has uncovered the fine details of excitation-contraction coupling under normal conditions while advances in genomics have helped to identify mutations in novel genes in patients with neuromuscular disorders. While it is now clear that many patients with congenital muscle diseases carry mutations in genes encoding proteins directly involved in Ca 2+ homeostasis, it has become apparent that mutations are also present in genes encoding for proteins not thought to be directly involved in Ca 2+ regulation. Ongoing research in the field now focuses on understanding the functional effect of individual mutations, as well as understanding the role of proteins not specifically located in the sarcoplasmic reticulum which nevertheless are involved in Ca 2+ regulation or excitation-contraction coupling. The principal challenge for the future is the identification of drug targets that can be pharmacologically manipulated by small molecules, with the ultimate aim to improve muscle function and quality of life of patients with congenital muscle disorders. The aim of this review is to give an overview of the most recent findings concerning Ca 2+ dysregulation and its impact on muscle function in patients with congenital muscle disorders due to mutations in proteins involved in excitation-contraction coupling and more broadly on Ca 2+ homeostasis.

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“…Furthermore, most general practitioners, emergency department physicians, hospital doctors, and intensivists do not associate (E)RM with MH; thus, consideration of RYR1 mutations as a cause may be easily forgotten. Although the incidence of fulminant MH during anaesthesia is relatively rare (with estimates between 1 in 4200 to 250,000), the incidence of RYR1 mutations with MHS in the general population might be up to 1 in 2000 [5]. This implies that there is a cohort of possible MH-Susceptible individuals who do never develop MH during general anaesthesia but may well present with ERM at one point in life.…”

Section: Malignant Hyperthermia (Mh)mentioning

confidence: 99%

“…Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are associated with a wide spectrum of inherited myopathies presenting throughout life [1], including dominantly inherited Central Core Disease (CCD) [2], and subgroups of recessively inherited Multi-minicore Disease (MmD) [3], Centronuclear Myopathy (CNM) [4] and Congenital Fibre Type Disproportion (CFTD) [5]. The dominantly inherited Malignant Hyperthermia Susceptibility (MHS) trait, a pharmacogenetic predisposition to severe and potentially life-threatening reactions in response to volatile anaesthetics and succinylcholine (for review, [6]), is an allelic condition; some patients with CCD may also be MH-susceptible, and MH-susceptible individuals may feature cores on muscle biopsy even without being weak.…”

Section: Introductionmentioning

confidence: 99%