A mutation in the human ryanodine receptor gene associated with central core disease

1993 ◽  
Vol 5 (1) ◽  
pp. 46-50 ◽  
Author(s):  
Yilin Zhang ◽  
Hai Shiene Chen ◽  
Vijay K. Khanna ◽  
Stella De Leon ◽  
Michael S. Phillips ◽  
...  
Keyword(s):  
Ryanodine Receptor ◽  
Receptor Gene ◽  
Central Core ◽  
Central Core Disease

scholarly journals Functional properties of ryanodine receptors carrying three amino acid substitutions identified in patients affected by multi-minicore disease and central core disease, expressed in immortalized lymphocytes

2006 ◽  
Vol 395 (2) ◽  
pp. 259-266 ◽  
Author(s):  
Sylvie Ducreux ◽  
Francesco Zorzato ◽  
Ana Ferreiro ◽  
Heinz Jungbluth ◽  
Francesco Muntoni ◽  
...  
Keyword(s):  
Amino Acid ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Receptor Gene ◽  
Receptor Activation ◽  
Central Core ◽  
Central Core Disease ◽  
Amino Acid Substitutions ◽  
Time Data ◽  
Minicore Disease

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.

Mutations in the ryanodine receptor gene in central core disease and malignant hyperthermia

1993 ◽  
Vol 5 (1) ◽  
pp. 51-55 ◽  
Author(s):  
K. A. Quane ◽  
J.M.S. Healy ◽  
K. E. Keating ◽  
B. M. Manning ◽  
F. J. Couch ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Receptor Gene ◽  
Central Core ◽  
Central Core Disease

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

2019 ◽  
Vol 317 (2) ◽  
pp. C358-C365 ◽  
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.

scholarly journals Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia

2017 ◽  
Vol 4 (2) ◽  
pp. 147-158 ◽  
Author(s):  
Remai Parker ◽  
Anja H. Schiemann ◽  
Elaine Langton ◽  
Terasa Bulger ◽  
Neil Pollock ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Functional Characterization ◽  
Central Core ◽  
Central Core Disease ◽  
Ryanodine Receptor 1

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

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0130606 ◽  
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

scholarly journals Functional Effects of Central Core Disease Mutations in the Cytoplasmic Region of the Skeletal Muscle Ryanodine Receptor

2001 ◽  
Vol 118 (3) ◽  
pp. 277-290 ◽  
Author(s):  
Guillermo Avila ◽  
Robert T. Dirksen
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Central Core ◽  
Central Core Disease ◽  
Calcium Release Channel ◽  
Release Channel ◽  
Voltage Gated ◽  
Channel Function ◽  
Store Depletion ◽  
The Impact

Central core disease (CCD) is a human myopathy that involves a dysregulation in muscle Ca2+ homeostasis caused by mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1), the protein that comprises the calcium release channel of the SR. Although genetic studies have clearly demonstrated linkage between mutations in RyR1 and CCD, the impact of these mutations on release channel function and excitation-contraction coupling in skeletal muscle is unknown. Toward this goal, we have engineered the different CCD mutations found in the NH2-terminal region of RyR1 into a rabbit RyR1 cDNA (R164C, I404M, Y523S, R2163H, and R2435H) and characterized the functional effects of these mutations after expression in myotubes derived from RyR1-knockout (dyspedic) mice. Resting Ca2+ levels were elevated in dyspedic myotubes expressing four of these mutants (Y523S > R2163H > R2435H R164C > I404M RyR1). A similar rank order was also found for the degree of SR Ca2+ depletion assessed using maximal concentrations of caffeine (10 mM) or cyclopiazonic acid (CPA, 30 μM). Although all of the CCD mutants fully restored L-current density, voltage-gated SR Ca2+ release was smaller and activated at more negative potentials for myotubes expressing the NH2-terminal CCD mutations. The shift in the voltage dependence of SR Ca2+ release correlated strongly with changes in resting Ca2+, SR Ca2+ store depletion, and peak voltage–gated release, indicating that increased release channel activity at negative membrane potentials promotes SR Ca2+ leak. Coexpression of wild-type and Y523S RyR1 proteins in dyspedic myotubes resulted in release channels that exhibited an intermediate degree of SR Ca2+ leak. These results demonstrate that the NH2-terminal CCD mutants enhance release channel sensitivity to activation by voltage in a manner that leads to increased SR Ca2+ leak, store depletion, and a reduction in voltage-gated Ca2+ release. Two fundamentally distinct cellular mechanisms (leaky channels and EC uncoupling) are proposed to explain how altered release channel function caused by different mutations in RyR1 could result in muscle weakness in CCD.

scholarly journals The Pore Region of the Skeletal Muscle Ryanodine Receptor Is a Primary Locus for Excitation-Contraction Uncoupling in Central Core Disease

2003 ◽  
Vol 121 (4) ◽  
pp. 277-286 ◽  
Author(s):  
Guillermo Avila ◽  
Kristen M. S. O'Connell ◽  
Robert T. Dirksen
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Central Core ◽  
Central Core Disease ◽  
Release Channel ◽  
Voltage Gated ◽  
Ryr1 Gene ◽  
Ec Coupling ◽  
Store Depletion ◽  
Sensor Activation

Human central core disease (CCD) is caused by mutations/deletions in the gene that encodes the skeletal muscle ryanodine receptor (RyR1). Previous studies have shown that CCD mutations in the NH2-terminal region of RyR1 lead to the formation of leaky SR Ca2+ release channels when expressed in myotubes derived from RyR1-knockout (dyspedic) mice, whereas a COOH-terminal mutant (I4897T) results in channels that are not leaky to Ca2+ but lack depolarization-induced Ca2+ release (termed excitation-contraction [EC] uncoupling). We show here that store depletion resulting from NH2-terminal (Y523S) and COOH-terminal (Y4795C) leaky CCD mutant release channels is eliminated after incorporation of the I4897T mutation into the channel (Y523S/I4897T and Y4795C/I4897T). In spite of normal SR Ca2+ content, myotubes expressing the double mutants lacked voltage-gated Ca2+ release and thus exhibited an EC uncoupling phenotype similar to that of I4897T-expressing myotubes. We also show that dyspedic myotubes expressing each of seven recently identified CCD mutations located in exon 102 of the RyR1 gene (G4890R, R4892W, I4897T, G4898E, G4898R, A4905V, R4913G) behave as EC-uncoupled release channels. Interestingly, voltage-gated Ca2+ release was nearly abolished (reduced ∼90%) while caffeine-induced Ca2+ release was only marginally reduced in R4892W-expressing myotubes, indicating that this mutation preferentially disrupts voltage-sensor activation of release. These data demonstrate that CCD mutations in exon 102 disrupt release channel permeation to Ca2+ during EC coupling and that this region represents a primary molecular locus for EC uncoupling in CCD.

Sign in / Sign up

Export Citation Format

Share Document