Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations

Eckhardt, Jan; Bachmann, Christoph; Benucci, Sofia; Elbaz, Moran; Ruiz, Alexis; Zorzato, Francesco; Treves, Susan

doi:10.1093/hmg/ddaa056

Cited by 5 publications

(8 citation statements)

References 39 publications

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“…As to the cause of the decreased RyR1 content in HO91 soleus muscles, it cannot be because of protein instability, as it would have occurred in all muscle types. In this context, it is interesting that the mechanical properties of extraocular muscles from HO91 mice were similar to those of WT littermates, as was the RyR1 protein level (23). The reduction in RyR1 and Ca v 1.1 may be caused at least in part by alterations of transcriptional regulation brought about by epigenetic modifications.…”

Section: Fiber Type Specificity Of the Muscle Phenotype Associated With The Bi-allelic Expression Of The Ryr1 Pa4329d Mutationmentioning

confidence: 92%

Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice

Elbaz

Ruiz

Nicolay

et al. 2020

Journal of Biological Chemistry

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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. Within the latter group, those carrying a hypomorphic mutation in one allele and a missense mutation in the other are the most severely affected. Because of nonsense-mediated decay, most hypomorphic alleles are not expressed, resulting in homozygous expression of the missense mutation allele. This should result in 50% reduced expression of the ryanodine receptor in skeletal muscle, but its observed content is even lower. 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. Our results revealed that 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. 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. In summary, bi-allelic expression of the RyR1 p.A4329D mutation phenotypically differs from monoallelic expression of this mutation in a compound heterozygous carrier.

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Section: Fiber Type Specificity Of the Muscle Phenotype Associated With The Bi-allelic Expression Of The Ryr1 Pa4329d Mutationmentioning

confidence: 92%

Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice

Elbaz

Ruiz

Nicolay

et al. 2020

Journal of Biological Chemistry

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“…Western blot analysis of Stim1 and Stim1L. Total homogenates of EDL, soleus and EOM muscles from WT mice were prepared in cracking buffer as previously described (16,17).…”

Section: Methodsmentioning

confidence: 99%

“…The muscle phenotype of the dHT mouse model closely resembles that of human patients carrying a hypomorphic allele plus a mis-sense RYR1 mutation, including reduced RyR1 protein content in skeletal muscles, the presence of cores and myofibrillar dis-array, mis-alignment of RyR1 and the dihydropyridine receptor and impaired EOM function (16, 17). Interestingly, beside a reduction in RyR1, the latter muscles also exhibited a significant decrease in mitochondrial number as well as changes in the expression and content of other proteins, including the almost complete absence of the EOM-specific MyHC isoform (17). Such results imply that broad changes in protein expression caused by the mutation and/or reduced content of RyR1 channels, impact other signaling pathways, leading to altered muscle function.…”

Section: Intructionmentioning

confidence: 99%

“…The double knock in mouse, henceforth referred to as double heterozygous or dHT mouse, carries the p.Q1970fsX16 mutation in one allele leading to the absence of a transcript due to nonsense-mediated decay of the allele carrying the frameshift mutation, and the mis-sense p.A4329D mutation in the other allele (16). The muscle phenotype of the dHT mouse model closely resembles that of human patients carrying a hypomorphic allele plus a mis-sense RYR1 mutation, including reduced RyR1 protein content in skeletal muscles, the presence of cores and myofibrillar dis-array, misalignment of RyR1 and the dihydropyridine receptor and impaired EOM function (16,17).…”

Section: Intructionmentioning

confidence: 99%

“…Interestingly, beside a reduction in RyR1, the latter muscles also exhibited a significant decrease in mitochondrial number as well as changes in the expression and content of other proteins, including the almost complete absence of the EOM-specific MyHC isoform (17).…”

Section: Intructionmentioning

confidence: 99%

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Quantitative proteomic analysis of skeletal muscles from wild type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies

Eckhardt

Ruiz

Koenig

et al. 2022

Preprint

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Skeletal muscle is a highly structured and differentiated tissue responsible for voluntary movement and metabolic regulation. Muscles however, are heterogeneous and depending on their location, speed of contraction, fatiguability and function, can be broadly subdivided into fast and slow twitch as well as subspecialized muscles, with each group expressing common as well as specific proteins. Congenital myopathies are a group of non-inflammatory non-dystrophic muscle diseases caused by mutations in a number of genes, leading to a weak muscle phenotype. In most cases specific muscles types are affected, with preferential involvement of fast twitch muscles as well as extraocular and facial muscles. Here we performed relative and absolute quantitative proteomic analysis of EDL, soleus and extraocular muscles from wild type and transgenic mice carrying compound heterozygous mutations in Ryr1 identified in a patient with a severe congenital myopathy. Our quantitative proteomic study shows that recessive Ryr1 mutations not only decrease the content of RyR1 protein in muscle, but also impact the content of many other proteins; in addition, we provide important insight into the pathological mechanism of congenital myopathies linked to mutations in other genes encoding components of the excitation contraction coupling molecular complex.

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A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice

Benucci,

Ruiz,

Franchini

et al. 2024

Journal of General Physiology

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RYR1 is the most commonly mutated gene associated with congenital myopathies, a group of early-onset neuromuscular conditions of variable severity. The functional effects of a number of dominant RYR1 mutations have been established; however, for recessive mutations, these effects may depend on multiple factors, such as the formation of a hypomorphic allele, or on whether they are homozygous or compound heterozygous. Here, we functionally characterize a new transgenic mouse model knocked-in for mutations identified in a severely affected child born preterm and presenting limited limb movement. The child carried the homozygous c.14928C>G RYR1 mutation, resulting in the p.F4976L substitution. In vivo and ex vivo assays revealed that homozygous mice fatigued sooner and their muscles generated significantly less force compared with their WT or heterozygous littermates. Electron microscopy, biochemical, and physiological analyses showed that muscles from RyR1 p.F4976L homozygous mice have the following properties: (1) contain fewer calcium release units and show areas of myofibrillar degeneration, (2) contain less RyR1 protein, (3) fibers show smaller electrically evoked calcium transients, and (4) their SR has smaller calcium stores. In addition, single-channel recordings indicate that RyR1 p.F4976L exhibits higher Po in the presence of 100 μM [Ca2+]. Our mouse model partly recapitulates the clinical picture of the homozygous human patient and provides significant insight into the functional impact of this mutation. These results will help understand the pathology of patients with similar RYR1 mutations.

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Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations

Cited by 5 publications

References 39 publications

Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice

Bi-allelic expression of the RyR1 p.A4329D mutation decreases muscle strength in slow-twitch muscles in mice

Quantitative proteomic analysis of skeletal muscles from wild type and transgenic mice carrying recessive Ryr1 mutations linked to congenital myopathies

A novel, patient-derived RyR1 mutation impairs muscle function and calcium homeostasis in mice

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