Dominant and recessive <i>RYR1</i> mutations in adults with core lesions and mild muscle symptoms

Duarte, Sofia; Oliveira, Jorge; Santos, Rosário; Pereira, Pedro; Barroso, Cândida; Conceição, Isabel; Evangelista, Teresinha

doi:10.1002/mus.22009

Cited by 39 publications

(22 citation statements)

References 34 publications

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“…Our results regarding common polymorphic RyR1 variants p.P1787L, p.G2060C and p.Q3756E are of interest since their functional significance remains unknown although these variants were detected in general population as well as in MH/CCD patients [21, 32, 43]. Bioinformatic analyses predicted p.Q3756E to be benign, whereas bioinformatic evaluation of possible functional impact of p.P1787L and p.G2060C variants using three software tools gave ambiguous results (Table 2).…”

Section: Discussionmentioning

confidence: 84%

Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease

Kraeva

Zvaritch

Rossi

et al. 2013

Neuromuscular Disorders

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Central core disease, one of the most common congenital myopathies in humans, has been linked to mutations in the RYR1 gene encoding the Ca2+ release channel of the sarcoplasmic reticulum (RyR1). Functional analyses showed that disease-associated RYR1 mutations led to impairment of skeletal muscle Ca2+ homeostasis, however, thorough understanding of the molecular mechanisms underlying central core disease and other RyR1-related conditions is still lacking. We screened by sequencing the complete RYR1 transcripts in ten unrelated patients with central core disease and identified five novel, p.M4640R, p.L4647P, p.F4808L, p.D4918N and p.F4941C, and four recurrent mutations. Four of the novel mutations involved amino acid residues that were positioned within putative transmembrane segments of the RyR1. The pathogenic character of the identified mutations was demonstrated by bioinformatic analyses and by the in vitro functional studies in HEK293 cells and RYR1-null (dyspedic) myotubes. Characterization of Ca2+ channel properties of RyR1s carrying one recurrent and two novel mutations upholds the view that diminished intracellular Ca2+ release caused by impaired Ca2+channel gating and/or Ca2+permeability is an important component of central core disease etiology. This study expands the list of functionally characterized disease-associated RyR1 mutations, increasing the value of genetic diagnosis for RyR1-related disorders.

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Section: Discussionmentioning

confidence: 84%

Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease

Kraeva

Zvaritch

Rossi

et al. 2013

Neuromuscular Disorders

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“…Duarte et al . 45 also reported p.3366R>H and p.3933Y>C inherited in cis in a patient with a family history of serious adverse reactions to anesthetics. These variants were considered pathogenic as they were not detected in 150 control samples and involve with phylogenetically conserved residues.…”

Section: Ryr1 Exon 91mentioning

confidence: 87%

“…RYR1 variants are discussed here in the context of MH. However RYR1 mutations are also known to be responsible for rare, congenital myopathies, which show both dominant and recessive modes of inheritance 44 such as autosomal recessive central core disease 45,46 . NGS will undoubtedly reveal variants of interest to a number of disorders.…”

Section: Discussionmentioning

confidence: 99%

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

et al. 2015

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Background Variants in RYR1 are associated with the majority of cases of malignant hyperthermia (MH), a form of heat illness pharmacogenetically triggered by general anesthetics, and they have also been associated with exertional heat illness. CACNA1S has also been implicated in MH. We applied a targeted next generation sequencing approach to identify variants in RYR1 and CACNA1S in a cohort of unrelated patients diagnosed with MH susceptibility. We also provide the first comprehensive report of sequencing of these two genes in a cohort of survivors of exertional heat illness. Methods DNA extracted from blood was genotyped using a “long” polymerase chain reaction technique, with sequencing on the Illumina GAII® or MiSeq® platforms (Illumina Inc., San Diego, CA). Variants were assessed for pathogenicity using bioinformatic approaches. For further follow up DNA from additional family members and up to 211 MH normal and 556 MH susceptible unrelated individuals was tested. Results In 29 MH patients we identified three pathogenic and four novel RYR1 variants, with a further five RYR1 variants previously reported in association with MH. Three novel RYR1 variants were found in the exertional heat illness cohort (n = 28) along with two more previously reported in association with MH. Two other variants were reported previously associated with centronuclear myopathy. We found one and three rare variants of unknown significance in CACNA1S in the MH and exertional heat illness cohorts respectively. Conclusion Targeted next generation sequencing proved efficient at identifying diagnostically useful and potentially implicated variants in RYR1 and CACNA1S in MH and exertional heat illness.

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“…8026C > T (p.Arg2676Trp) (on two alleles)11YesNoPathogenicLikely pathogenicGillard [33]; Girard [34] for first mutationGuis (2004) [35] for second mutationc.2488C > T (p.Arg830Trp)c.10219G > A (p.Ala3407Thr) (on two alleles)11NoNoVUSVUSSnoeck [21]Molenaar [36]c.4178A > G (p.Lys1393Arg)c.14210G > A (p.Arg4737Gln) (on two alleles)11NoVUSLikely pathogenicDlamini [5]Monnier [37]; Gomez [38]c.4711A > G (p.Ile1571Val)c.10097G > A (p.Arg3366His)c.11798A > G (p.Tyr3933Cys) (on one allele)22NoVUSVUSVUSTammaro [39]; Kraeva [28]Duarte [40]; Kraeva [28]Gillies [41]; Kraeva [28]c.6385G > A (p.Asp2129Asn)11NoVUSDlamini [5]c.6502G > A (p.Val2168Met)11YesPathogenicManning [42]; Girard [34]c.6617C > T (p.Thr2206Met)11YesPathogenicManning [42]; Murayama [43]c.6838G > A (p.Val2280Ile)11NoLikely benignGalli [44]c.7025A > G (p.Asn2...…”

Section: Resultsmentioning

confidence: 99%

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

et al. 2019

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ObjectiveThe histopathological features of malignant hyperthermia (MH) and non-anaesthetic (mostly exertional) rhabdomyolysis (RM) due to RYR1 mutations have only been reported in a few cases.MethodsWe performed a retrospective multi-centre cohort study focussing on the histopathological features of patients with MH or RM due to RYR1 mutations (1987–2017). All muscle biopsies were reviewed by a neuromuscular pathologist. Additional morphometric and electron microscopic analysis were performed where possible.ResultsThrough the six participating centres we identified 50 patients from 46 families, including patients with MH (n = 31) and RM (n = 19). Overall, the biopsy of 90% of patients showed one or more myopathic features including: increased fibre size variability (n = 44), increase in the number of fibres with internal nuclei (n = 30), and type I fibre predominance (n = 13). Abnormalities on oxidative staining, generally considered to be more specifically associated with RYR1-related congenital myopathies, were observed in 52%, and included unevenness (n = 24), central cores (n = 7) and multi-minicores (n = 3). Apart from oxidative staining abnormalities more frequently observed in MH patients, the histopathological spectrum was similar between the two groups. There was no correlation between the presence of cores and the occurrence of clinically detectable weakness or presence of (likely) pathogenic variants.ConclusionsPatients with RYR1-related MH and RM exhibit a similar histopathological spectrum, ranging from mild myopathic changes to cores and other features typical of RYR1-related congenital myopathies. Suggestive histopathological features may support RYR1 involvement, also in cases where the in vitro contracture test is not informative.Electronic supplementary materialThe online version of this article (10.1007/s00415-019-09209-z) contains supplementary material, which is available to authorized users.

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Dominant and recessive RYR1 mutations in adults with core lesions and mild muscle symptoms

Cited by 39 publications

References 34 publications

Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease

Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease

Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations

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