A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene

More than 80 mutations in the skeletal muscle ryanodine receptor gene have been found to be associated with autosomal dominant forms of malignant hyperthermia and central core disease, and with recessive forms of multi-minicore disease. Studies on the functional effects of pathogenic dominant mutations have shown that they mostly affect intracellular Ca2+ homoeostasis, either by rendering the channel hypersensitive to activation (malignant hyperthermia) or by altering the amount of Ca2+ released subsequent to physiological or pharmacological activation (central core disease). In the present paper, we show, for the first time, data on the functional effect of two recently identified recessive ryanodine receptor 1 amino acid substitutions, P3527S and V4849I, as well as that of R999H, another substitution that was identified in two siblings that were affected by multi-minicore disease. We studied the intracellular Ca2+ homoeostasis of EBV (Epstein–Barr virus)-transformed lymphoblastoid cells from the affected patients, their healthy relatives and control individuals. Our results show that the P3527S substitution in the homozygous state affected the amount of Ca2+ released after pharmacological activation with 4-chloro-m-cresol and caffeine, but did not affect the size of the thapsigargin-sensitive Ca2+ stores. The other substitutions had no effect on either the size of the intracellular Ca2+ stores, or on the amount of Ca2+ released after ryanodine receptor activation; however, both the P3527S and V4849I substitutions had a small but significant effect on the resting Ca2+ concentration.

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Divergent Activity Profiles of Type 1 Ryanodine Receptor Channels Carrying Malignant Hyperthermia and Central Core Disease Mutations in the Amino-Terminal Region

PLoS ONE ◽

10.1371/journal.pone.0130606 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0130606 ◽

Cited By ~ 23

Author(s):

Takashi Murayama ◽

Nagomi Kurebayashi ◽

Toshiko Yamazawa ◽

Hideto Oyamada ◽

Junji Suzuki ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Terminal Region ◽

Central Core ◽

Central Core Disease ◽

Amino Terminal ◽

Disease Mutations

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Type 1 ryanodine receptor knock-in mutation causing central core disease of skeletal muscle also displays a neuronal phenotype

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1115111108 ◽

2011 ◽

Vol 109 (2) ◽

pp. 610-615 ◽

Cited By ~ 20

Author(s):

V. De Crescenzo ◽

K. E. Fogarty ◽

J. J. Lefkowitz ◽

K. D. Bellve ◽

E. Zvaritch ◽

...

Keyword(s):

Skeletal Muscle ◽

Ryanodine Receptor ◽

Central Core ◽

Central Core Disease ◽

Neuronal Phenotype

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Identification of variants of the ryanodine receptor type 1 in patients with exertional heat stroke and positive response to the malignant hyperthermia in vitro contracture test

British Journal of Anaesthesia ◽

10.1093/bja/aew047 ◽

2016 ◽

Vol 116 (4) ◽

pp. 566-568 ◽

Cited By ~ 18

Author(s):

N Roux-Buisson ◽

N Monnier ◽

E Sagui ◽

A Abriat ◽

C Brosset ◽

...

Keyword(s):

Malignant Hyperthermia ◽

Ryanodine Receptor ◽

Positive Response ◽

Heat Stroke ◽

Receptor Type ◽

Exertional Heat Stroke ◽

In Vitro Contracture Test

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Early Findings in Neonatal Cases of RYR1–Related Congenital Myopathies

Frontiers in Neurology ◽

10.3389/fneur.2021.664618 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eleonora Mauri ◽

Daniela Piga ◽

Alessandra Govoni ◽

Roberta Brusa ◽

Serena Pagliarani ◽

...

Keyword(s):

Ryanodine Receptor ◽

Brain Mri ◽

Fetal Brain ◽

Congenital Myopathy ◽

Receptor Type ◽

Congenital Myopathies ◽

Muscle Mri ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Ryanodine receptor type 1-related congenital myopathies are the most represented subgroup among congenital myopathies (CMs), typically presenting a central core or multiminicore muscle histopathology and high clinical heterogeneity. We evaluated a cohort of patients affected with Ryanodine receptor type 1-related congenital myopathy (RYR1-RCM), focusing on four patients who showed a severe congenital phenotype and underwent a comprehensive characterization at few months of life. To date there are few reports on precocious instrumental assessment. In two out of the four patients, a muscle biopsy was performed in the first days of life (day 5 and 37, respectively) and electron microscopy was carried out in two patients detecting typical features of congenital myopathy. Two patients underwent brain MRI in the first months of life (15 days and 2 months, respectively), one also a fetal brain MRI. In three children electromyography was performed in the first week of life and neurogenic signs were excluded. Muscle MRI obtained within the first years of life showed a typical pattern of RYR1-CM. The diagnosis was confirmed through genetic analysis in three out of four cases using Next Generation Sequencing (NGS) panels. The development of a correct and rapid diagnosis is a priority and may lead to prompt medical management and helps optimize inclusion in future clinical trials.

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Amino Acid Residues Gln4020and Lys4021of the Ryanodine Receptor Type 1 Are Required for Activation by 4-Chloro-m-cresol

Journal of Biological Chemistry ◽

10.1074/jbc.m600670200 ◽

2006 ◽

Vol 281 (30) ◽

pp. 21022-21031 ◽

Cited By ~ 18

Author(s):

James D. Fessenden ◽

Wei Feng ◽

Isaac N. Pessah ◽

Paul D. Allen

Keyword(s):

Amino Acid ◽

Ryanodine Receptor ◽

Receptor Type ◽

Amino Acid Residues

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Interactions of Dichlorodiphenyltrichloroethane (DDT) and Dichlorodiphenyldichloroethylene (DDE) With Skeletal Muscle Ryanodine Receptor Type 1

Toxicological Sciences ◽

10.1093/toxsci/kfz120 ◽

2019 ◽

Vol 170 (2) ◽

pp. 509-524

Author(s):

Kim M Truong ◽

Gennady Cherednichenko ◽

Isaac N Pessah

Keyword(s):

Skeletal Muscle ◽

Ryanodine Receptor ◽

Membrane Vesicles ◽

Receptor Type ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Voltage Gated Sodium Channels ◽

Muscle Health ◽

Living Organisms

Abstract Dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) are ubiquitous in the environment and detected in tissues of living organisms. Although DDT owes its insecticidal activity to impeding closure of voltage-gated sodium channels, it mediates toxicity in mammals by acting as an endocrine disruptor (ED). Numerous studies demonstrate DDT/DDE to be EDs, but studies examining muscle-specific effects mediated by nonhormonal receptors in mammals are lacking. Therefore, we investigated whether o,p′-DDT, p,p′-DDT, o,p′-DDE, and p,p′-DDE (DDx, collectively) alter the function of ryanodine receptor type 1 (RyR1), a protein critical for skeletal muscle excitation-contraction coupling and muscle health. DDx (0.01–10 µM) elicited concentration-dependent increases in [3H]ryanodine ([3H]Ry) binding to RyR1 with o,p′-DDE showing highest potency and efficacy. DDx also showed sex differences in [3H]Ry-binding efficacy toward RyR1, where [3H]Ry-binding in female muscle preparations was greater than male counterparts. Measurements of Ca2+ transport across sarcoplasmic reticulum (SR) membrane vesicles further confirmed DDx can selectively engage with RyR1 to cause Ca2+ efflux from SR stores. DDx also disrupts RyR1-signaling in HEK293T cells stably expressing RyR1 (HEK-RyR1). Pretreatment with DDx (0.1–10 µM) for 100 s, 12 h, or 24 h significantly sensitized Ca2+-efflux triggered by RyR agonist caffeine in a concentration-dependent manner. o,p′-DDE (24 h; 1 µM) significantly increased Ca2+-transient amplitude from electrically stimulated mouse myotubes compared with control and displayed abnormal fatigability. In conclusion, our study demonstrates DDx can directly interact and modulate RyR1 conformation, thereby altering SR Ca2+-dynamics and sensitize RyR1-expressing cells to RyR1 activators, which may ultimately contribute to long-term impairments in muscle health.

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Homer Regulates Gain of Ryanodine Receptor Type 1 Channel Complex

Journal of Biological Chemistry ◽

10.1074/jbc.m207675200 ◽

2002 ◽

Vol 277 (47) ◽

pp. 44722-44730 ◽

Cited By ~ 103

Author(s):

Wei Feng ◽

Jiancheng Tu ◽

Tianzhong Yang ◽

Patty Shih Vernon ◽

Paul D. Allen ◽

...

Keyword(s):

Ryanodine Receptor ◽

Receptor Type

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A central core disease mutation in the Ca2+-binding site of skeletal muscle ryanodine receptor impairs single-channel regulation

AJP Cell Physiology ◽

10.1152/ajpcell.00052.2019 ◽

2019 ◽

Vol 317 (2) ◽

pp. C358-C365 ◽

Cited By ~ 3

Author(s):

Venkat R. Chirasani ◽

Le Xu ◽

Hannah G. Addis ◽

Daniel A. Pasek ◽

Nikolay V. Dokholyan ◽

...

Keyword(s):

Skeletal Muscle ◽

Amino Acid ◽

Missense Mutation ◽

Ryanodine Receptor ◽

Single Channel ◽

Central Core ◽

Central Core Disease ◽

Hek293 Cells ◽

Amino Acid Residues ◽

Single Channel Recordings

Cryoelectron microscopy and mutational analyses have shown that type 1 ryanodine receptor (RyR1) amino acid residues RyR1-E3893, -E3967, and -T5001 are critical for Ca2+-mediated activation of skeletal muscle Ca2+ release channel. De novo missense mutation RyR1-Q3970K in the secondary binding sphere of Ca2+ was reported in association with central core disease (CCD) in a 2-yr-old boy. Here, we characterized recombinant RyR1-Q3970K mutant by cellular Ca2+ release measurements, single-channel recordings, and computational methods. Caffeine-induced Ca2+ release studies indicated that RyR1-Q3970K formed caffeine-sensitive, Ca2+-conducting channel in HEK293 cells. However, in single-channel recordings, RyR1-Q3970K displayed low Ca2+-dependent channel activity and greatly reduced activation by caffeine or ATP. A RyR1-Q3970E mutant corresponds to missense mutation RyR2-Q3925E associated with arrhythmogenic syndrome in cardiac muscle. RyR1-Q3970E also formed caffeine-induced Ca2+ release in HEK293 cells and exhibited low activity in the presence of the activating ligand Ca2+ but, in contrast to RyR1-Q3970K, was activated by ATP and caffeine in single-channel recordings. Computational analyses suggested distinct structural rearrangements in the secondary binding sphere of Ca2+ of the two mutants, whereas the interaction of Ca2+ with directly interacting RyR1 amino acid residues Glu3893, Glu3967, and Thr5001 was only minimally affected. We conclude that RyR1-Q3970 has a critical role in Ca2+-dependent activation of RyR1 and that a missense RyR1-Q3970K mutant may give rise to myopathy in skeletal muscle.

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