A new mutation in the skeletal ryanodine receptor gene (RYR1) is potentially causative of malignant hyperthermia, central core disease, and severe skeletal malformation

2003 ◽  
Vol 124A (3) ◽  
pp. 248-254 ◽  
Author(s):  
Henrik Rueffert ◽  
Derk Olthoff ◽  
Christine Deutrich ◽  
Ralf Schober ◽  
Ursula G. Froster
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Receptor Gene ◽  
Central Core ◽  
Central Core Disease ◽  
New Mutation ◽  
Skeletal Malformation

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 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 Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease

2017 ◽  
Vol 474 (16) ◽  
pp. 2749-2761 ◽  
Author(s):  
Wenqian Chen ◽  
Andrea Koop ◽  
Yingjie Liu ◽  
Wenting Guo ◽  
Jinhong Wei ◽  
...  
Keyword(s):  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Term Treatment ◽  
Central Core ◽  
Central Core Disease ◽  
Hek293 Cells ◽  
Polymorphic Ventricular Tachycardia ◽  
Long Term Treatment ◽  
The Impact ◽  
Common Defect

Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and central core disease (CCD), whereas mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most disease-associated RyR1 and RyR2 mutations are located in the N-terminal, central, and C-terminal regions of the corresponding ryanodine receptor (RyR) isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca2+ release during store Ca2+ overload, a process known as store overload-induced Ca2+ release (SOICR). Considering the similar locations of disease-associated RyR1 and RyR2 mutations in the RyR structure, we hypothesize that like CPVT-associated RyR2 mutations, MH/CCD-associated RyR1 mutations also enhance SOICR. To test this hypothesis, we determined the impact on SOICR of 12 MH/CCD-associated RyR1 mutations E2347-del, R2163H, G2434R, R2435L, R2435H, and R2454H located in the central region, and Y4796C, T4826I, L4838V, A4940T, G4943V, and P4973L located in the C-terminal region of the channel. We found that all these RyR1 mutations reduced the threshold for SOICR. Dantrolene, an acute treatment for MH, suppressed SOICR in HEK293 cells expressing the RyR1 mutants R164C, Y523S, R2136H, R2435H, and Y4796C. Interestingly, carvedilol, a commonly used β-blocker that suppresses RyR2-mediated SOICR, also inhibits SOICR in these RyR1 mutant HEK293 cells. Therefore, these results indicate that a reduced SOICR threshold is a common defect of MH/CCD-associated RyR1 mutations, and that carvedilol, like dantrolene, can suppress RyR1-mediated SOICR. Clinical studies of the effectiveness of carvedilol as a long-term treatment for MH/CCD or other RyR1-associated disorders may be warranted.

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

Protocol for the Sequence Analysis of Ryanodine Receptor Subtype 1 Gene Transcripts from Human Leukocytes

2003 ◽  
Vol 99 (2) ◽  
pp. 289-296 ◽  
Author(s):  
Natasha Kraev ◽  
Julian C. P. Loke ◽  
Alexander Kraev ◽  
David H. MacLennan
Keyword(s):  
Sequence Analysis ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Blood ◽  
Messenger Rna ◽  
Central Core ◽  
Central Core Disease ◽  
Receptor Subtype ◽  
Novel Mutations ◽  
Ryr1 Gene

Background The search for novel mutations in the ryanodine receptor subtype 1 (RYR1) gene causing malignant hyperthermia and central core disease is hampered by the fact that the gene contains 106 exons. Searching for novel mutations in complementary DNA (cDNA) requires an invasive muscle biopsy. Accordingly, an alternate source of RYR1 cDNA was sought for sequence analysis. Methods Leukocytes were isolated from human blood and used for extraction of RNA and reverse transcription of messenger RNA into cDNA. A detailed protocol was developed in which overlapping fragments of RYR1 cDNA were amplified by polymerase chain reaction in a series of steps and used for double-strand sequencing. Results The sequences of full-length leukocyte RYR1 cDNA obtained from four human blood samples were shown to be identical to the sequence of a human muscle RYR1 cDNA. The incidence of aberrant splicing was more pronounced in the blood-derived cDNAs, but this could be minimized by adequate sample preparation. Protocols to sequence alternatively spliced products were also developed. Several silent nucleotide polymorphisms were detected, and minor revisions were made to the RYR1 sequence. Conclusions Because there are no differences in RYR1 transcript structure between muscle and leukocytes, aside from those that may be ascribed to RNA splicing aberrations during processing, leukocytes seem to be an adequate substitute tissue for screening the RYR1 gene for previously undiscovered mutations in families with malignant hyperthermia or central core disease.

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