King–Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene

Dowling, James J.; Lillis, Suzanne; Amburgey, K.; Zhou, Haïyan; Al‐Sarraj, Safa; Buk, Stefan; Wraige, Elizabeth; Chow, Gabby; Abbs, Stephen; Leber, Steven M.; Lachlan, Katherine; Baralle, Diana; Taylor, Alexandra; Sewry, Caroline A.; Muntoni, Francesco; Jungbluth, Heinz

doi:10.1016/j.nmd.2011.03.006

Cited by 101 publications

(74 citation statements)

References 28 publications

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“…As with MHS, these dynamic conditions can also exist in the absence of overt muscle weakness. Lastly, there are also particular clinical syndromes that are associated, at least in part, with RYR1 mutations; these include King-Denborough syndrome (KDS) and late-onset axial myopathy [28,29].…”

Section: Ryr1-related Myopathiesmentioning

confidence: 99%

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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%

“…One potential allelic phenotype is KDS, a condition that shares many similarities to NAM including weakness, an unusual gait, and MH susceptibility. To date, only RYR1 mutations have been found as a cause KDS, though they do not account for all cases [28].…”

Section: How Is It Treated?mentioning

confidence: 99%

Triadopathies: An Emerging Class of Skeletal Muscle Diseases

2014

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“…Many individuals with Native American myopathy however, present a phenotype that is reminiscent of that of patients with RYR1 mutations, including progressive scoliosis, short stature and dysmorphic features resembling RYR1-related King Denborough syndrome KDS [67,68]. The first report regarding the underlying molecular mechanism of this disorder was the identification of the recessive STAC3 p.W284 S mutation in patients with Native American myopathy.…”

Section: Stac3 Mutations and Native American Myopathymentioning

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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“…36 Along the same lines, King-Denborough syndrome, another RYR1-related myopathy with dysmorphic features, has recently been attributed to compound heterozygositiy for a dominant MH mutation running in the family and a second RYR1 variant in the child not always detected on traditional sequencing but reducing the amount of functional RyR1 protein. 37 These examples illustrate a complex inheritance pattern associated with RYR1-related disorders, with some RYR1 mutations behaving as dominants with regards to the MHS trait but as recessives with regards to congenital myopathy phenotypes. Pathogenicity can only be reliably assigned and predicted if sequencing of the entire RYR1 gene has been performed and all RYR1 variants potentially contributing to a at risk genotype have been identified.…”

Section: Positive Clinical Predictive Value (Lifetime Risk To Developmentioning

confidence: 99%