Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm

Treves, Susan; Jungbluth, Heinz; Muntoni, Francesco; Zorzato, Francesco

doi:10.1016/j.coph.2008.01.005

Cited by 158 publications

(148 citation statements)

References 62 publications

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“…A single dominant missense mutation, Y128C, in the GlyR ␣1 subunit LBD, resulted in tonic channel opening in the absence of agonist. Spontaneous channel activity has been recognized as a pathogenic mechanism in other episodic disorders including congenital muscle disease, cardiac arrhythmias, and hypokalemic periodic paralysis (Paavola et al, 2007;Sokolov et al, 2007;Treves et al, 2008). Previous GlyR ␣1 site-directed mutagenesis studies have also identified three residues causing spontaneously opening: D97R and F99A in the LBD and A288W in M3 (Mihic et al, 1997;Beckstead et al, 2002;Miller et al, 2008).…”

mentioning

confidence: 99%

Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

Chung¹,

Vanbellinghen²,

Mullins³

et al. 2010

Journal of Neuroscience

116

152

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Hyperekplexia is a rare, but potentially fatal, neuromotor disorder characterized by exaggerated startle reflexes and hypertonia in response to sudden, unexpected auditory or tactile stimuli. This disorder is primarily caused by inherited mutations in the genes encoding the glycine receptor (GlyR) ␣1 subunit (GLRA1) and the presynaptic glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of GLRA1 in 88 new unrelated human hyperekplexia patients revealed 19 sequence variants in 30 index cases, of which 21 cases were inherited in recessive or compound heterozygote modes. This indicates that recessive hyperekplexia is far more prevalent than previous estimates. From the 19 GLRA1 sequence variants, we have investigated the functional effects of 11 novel and 2 recurrent mutations. The expression levels and functional properties of these hyperekplexia mutants were analyzed using a high-content imaging system and patch-clamp electrophysiology. When expressed in HEK293 cells, either as homomeric ␣1 or heteromeric ␣1␤ GlyRs, subcellular localization defects were the major mechanism underlying recessive mutations. However, mutants without trafficking defects typically showed alterations in the glycine sensitivity suggestive of disrupted receptor function. This study also reports the first hyperekplexia mutation associated with a GlyR leak conductance, suggesting tonic channel opening as a new mechanism in neuronal ligand-gated ion channels.

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mentioning

confidence: 99%

Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

Chung¹,

Vanbellinghen²,

Mullins³

et al. 2010

Journal of Neuroscience

116

152

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“…The first 4000 amino acids make up the large cytoplasmic domain that contains binding sites for various modulators, while the last 1000 amino acids constitute the carboxy terminal pore-forming domain [21,22]. Dominant and recessive mutations in RYR1, the gene encoding the RyR1, are associated with a range of early-onset neuromuscular disorders including the core myopathies central core disease (CCD) and multi-minicore disease (MmD), congenital fiber type disproportion, (CFTD) centronuclear myopathy (CNM), exertional rhabdomyolysis/myalgia as well as the pharmacogenetic disorder malignant hyperthermia (MH) [23][24][25][26].…”

Section: Excitation-contraction Couplingmentioning

confidence: 99%

“…Since this initial discovery in the early 90s, more than 200 mutations have been identified in patients with a variety of inherited myopathies including MHS, exertional rhabdomyolysis/myalgia and a range of congenital myopathies including CCD, as well as subgroups of MmD, CNM and CFTD [23][24][25][26]. Because of the sheer size of the RYR1 gene which spans 106 exons and >15 kb DNA, initial mutation searches were confined to hotspot domains originally implicated in autosomal dominant MHS and CCD.…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

“…The calculated frequency of RYR1 mutations is approximately 1:3000 making it one of the most commonly mutated genes associated with neuromuscular disorders [38][39][40]. A number of reviews concerning the frequency, disease associations and functional impact of RYR1 mutations have been published in recent years and the reader is referred to these for a more in depth description (for example see [12][13][14][15][16][17][18][19][20][21][22][23][24][41][42][43][44][45]). The disease phenotype resulting from RYR1 mutations largely depends on their location within the RYR1 coding sequence and whether the mutations are dominant or recessive.…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

“…For gain-of-function dominant MHS-linked mutations that render the Ca 2+ channel hypersensitive and thus more prone to be in the open conformation, the amino acid substitutions induce local protein misfolding or affect the intersubunit domain-domain interfaces; the resulting tetrameric channels are deregulated leading to a leak of Ca 2+ into the cytoplasm or to an excessive amount of Ca 2+ release from the SR [22,24,[46][47][48][49]. This results in a number of direct effects in the muscle fibers including a higher resting cytosolic [Ca 2+ ], a shift in the sensitivity to activating signals (depolarization, pharmacological stimulation) or greater depolarization-induced Ca 2+ influx, all of which can lead to a hypermetabolic state which is the underlying feature of MHS.…”

Section: Disorders Associated With Ryr1 Mutationsmentioning

confidence: 99%

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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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Genetics of Muscle Disease

2013

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Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm

Abstract: SummaryDysregulation of calcium signals due to defects of the skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease

Cited by 158 publications

References 62 publications

Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

Pathophysiological Mechanisms of Dominant and Recessive GLRA1 Mutations in Hyperekplexia

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

Genetics of Muscle Disease

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