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Link to original content: https://omim.org/entry/180901
Alternative titles; symbols
HGNC Approved Gene Symbol: RYR1
SNOMEDCT: 764957003; ICD10CM: G71.29;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38) : 19:38,433,691-38,587,564 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | {Malignant hyperthermia susceptibility 1} | 145600 | Autosomal dominant | 3 |
| Congenital myopathy 1A, autosomal dominant, with susceptibility to malignant hyperthermia | 117000 | Autosomal dominant | 3 | |
| Congenital myopathy 1B, autosomal recessive | 255320 | Autosomal recessive | 3 | |
| King-Denborough syndrome | 619542 | Autosomal dominant | 3 |
The RYR1 gene encodes the skeletal muscle ryanodine receptor, which serves as a calcium release channel of the sarcoplasmic reticulum as well as a bridging structure connecting the sarcoplasmic reticulum and transverse tubule (MacLennan et al., 1989).
See also RYR2 (180902) and RYR3 (180903), which encode the cardiac and brain ryanodine receptors, respectively.
MacLennan et al. (1989) and Zorzato et al. (1990) cloned cDNAs encoding the rabbit and human ryanodine receptors. The human cDNA encodes a 5,032-amino acid protein with a molecular mass of 563.5 kD, which is made without an N-terminal sequence. Sequence analysis predicts 10 potential transmembrane sequences in the C-terminal region and 2 additional potential transmembrane sequences closer to the center of the molecule, which could form the calcium-conducting pore. The remainder of the protein is hydrophilic and presumably constitutes the cytoplasmic domain. Several potential calmodulin (see 114180)-binding sites were observed between residues 2800 and 3050.
Eu et al. (2000) reported that ambient oxygen tension (pO2) dynamically controls the redox state of 6 to 8 out of 50 thiols in each RYR1 subunit and thereby tunes the response to NO. At physiologic pO2, nanomolar NO activates the channel by S-nitrosylating a single cysteine residue. Among sarcoplasmic reticulum proteins, S-nitrosylation is specific to RYR1, and its effect on the channel is calmodulin (see 114180) dependent. Neither activation nor S-nitrosylation of the channel occurs at ambient pO2. The demonstration that channel cysteine residues subserve coupled O2 sensor and NO regulatory functions, and that these operate through the prototypic allosteric effector calmodulin, may have general implications for the regulation of redox-related systems.
Calcium-induced calcium release is a general mechanism that most cells use to amplify calcium signals. In heart cells, this mechanism is operated between voltage-gated L-type calcium channels (LCCs; see 114205) in the plasma membrane and calcium release channels, commonly known as ryanodine receptors, in the sarcoplasmic reticulum. The calcium influx through LCCs traverses a cleft of roughly 12 nm formed by the cell surface and the sarcoplasmic reticulum membrane, and activates adjacent ryanodine receptors to release calcium in the form of calcium sparks (Cheng et al., 1993). Wang et al. (2001) determined the kinetics, fidelity, and stoichiometry of coupling between LCCs and ryanodine receptors. They showed that the local calcium signal produced by a single opening of an LCC, named a 'calcium sparklet,' can trigger about 4 to 6 ryanodine receptors to generate a calcium spark. The coupling between LCCs and ryanodine receptors is stochastic, as judged by the exponential distribution of the coupling latency. The fraction of sparklets that successfully triggers a spark is less than unity and declines in a use-dependent manner.
Ducreux et al. (2004) found that activation of RYR1 caused release of interleukin-6 (IL6; 147620) from cultured human myotubes. Maximal release was obtained 4 to 6 hours later, suggesting that IL6 was newly transcribed and synthesized.
Epigenetic regulation of gene expression is a source of genetic variation, which can mimic recessive mutations by creating transcriptional haploinsufficiency. Germline epimutations and genomic imprinting are typical examples. Genomic imprinting can be tissue-specific, with biallelic expression in some tissues and monoallelic expression in others or with polymorphic expression in the general population. During the RYR1 mutation analysis of a cohort of patients with recessive core myopathies, Zhou et al. (2006) discovered that 6 (55%) of 11 patients had monoallelic RYR1 transcription in skeletal muscle, despite being heterozygous at the genomic level. In families for which parental DNA was available, segregation studies showed that the nonexpressed allele was maternally inherited. Transcription analysis in patients' fibroblasts and lymphoblastoid cell lines indicated biallelic expression, which suggested tissue-specific silencing. Transcription analysis of normal human fetal tissues showed that RYR1 is monoallelically expressed in skeletal and smooth muscle, brain, and eye in 10% of cases. In contrast, 25 normal adult human skeletal muscle samples displayed only biallelic expression. Finally, the administration of the DNA methyltransferase inhibitor 5-aza-deoxycytidine to cultured patient skeletal muscle myoblasts reactivated the transcription of the silenced allele, which suggested hypermethylation as a mechanism for RYR1 silencing. The data indicated that RYR1 undergoes polymorphic, tissue-specific, and developmentally regulated allele silencing and that this unveils recessive mutations in patients with core myopathies. The data also suggested that imprinting is a likely mechanism for this phenomenon and that similar mechanisms could play a role in human phenotypic heterogeneity. Klein et al. (2012) found that some of the patients reported by Zhou et al. (2006) with apparent mutations expressed monoallelically in the skeletal muscle were found to have another stop RYR1 mutation, resulting in nonsense-mediated mRNA decay and lack of expression.
Phillips et al. (1996) reported that the RYR1 gene contains 106 exons, of which 2 are alternatively spliced. The length of the gene was estimated to be approximately 160 kb. The numbering of the nucleotides comprising the RYR1 cDNA and the numbering of amino acids encoded by them were corrected to account for earlier errors and omissions.
Crystal Structure
Tung et al. (2010) showed the 2.5-angstrom resolution crystal structure of a region spanning 3 domains of RyR1, encompassing amino acid residues 1-559. The domains interact with each other through a predominantly hydrophilic interface. Docking in RyR1 electron microscopy maps unambiguously places the domains in the cytoplasmic portion of the channel, forming a 240-kD cytoplasmic vestibule around the 4-fold symmetry axis. Tung et al. (2010) pinpointed the exact locations of more than 50 disease-associated mutations in full-length RyR1 and RyR2 (180902). The mutations can be classified into 3 groups: those that destabilize the interfaces between the 3 amino-terminal domains, disturb the folding of individual domains, or affect 1 of the 6 interfaces with other parts of the receptor. Tung et al. (2010) proposed a model whereby the opening of RyR coincides with allosterically couples motions within the N-terminal domains. This process can be affected by mutations that target various interfaces within and across subunits. Tung et al. (2010) suggested that the crystal structure provides a framework to understand the many disease-associated mutations in RyRs that have been studied using functional methods, and would be useful for developing new strategies to modulate RyR function in disease states.
Using electron cryomicroscopy, Efremov et al. (2015) determined the architecture of rabbit Ryr1 at a resolution of 6.1 angstroms and showed that the cytoplasmic moiety of Ryr1 contains 2 large alpha-solenoid domains and several smaller domains, with folds suggestive of participation in protein-protein interactions. The transmembrane domain represents a chimera of voltage-gated sodium and pH-activated ion channels. Efremov et al. (2015) identified the calcium-binding EF-hand domain and showed that it functions as a conformational switch allosterically gating the channel.
Zalk et al. (2015) reported the closed-state structure of the 2.3-megadalton complex of rabbit Ryr1, solved by single-particle electron cryomicroscopy at an overall resolution of 4.8 angstroms. They fitted a polyalanine-level model to all 3,757 ordered residues in each protomer, defining the transmembrane pore in great detail and placing all cytosolic domains as tertiary folds. The cytosolic assembly is built on an extended alpha-solenoid scaffold connecting key regulatory domains to the pore. The Ryr1 pore architecture places it in the 6-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF hands originating from the alpha-solenoid scaffold, suggesting a mechanism for channel gating by calcium.
Yan et al. (2015) reported the structure of rabbit Ryr1 in complex with its modulator FKBP12 (186945) at an overall resolution of 3.8 angstroms, determined by single-particle electron cryomicroscopy. Three domains, named central, handle, and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The 4 elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. Yan et al. (2015) concluded that these structural features explain high ion conductance by ryanodine receptors and the long-range allosteric regulation of channel activities.
By in situ hybridization, MacLennan et al. (1989) localized the RYR1 gene to chromosome 19cen-q13.2. By fluorescence in situ hybridization, Trask et al. (1993) assigned the RYR1 gene to 19q13.1. MacKenzie et al. (1990) mapped the RYR1 gene to 19q13.1, distal to GPI (172400) and MAG (159460).
Using somatic cell hybrids, Harbitz et al. (1990) regionalized the porcine Ryr1 gene (termed CRC by them) to chromosome 6p11-q21. The authors noted homology of synteny with the genes on human chromosome 19.
Cavanna et al. (1990) demonstrated that the Ryr gene in the mouse maps to chromosome 7. By in situ hybridization, Mattei et al. (1994) mapped the mouse Ryr1 gene to 7A2-7A3.
Robinson et al. (2006) provided a detailed review of mutations in the RYR1 gene.
Susceptibility to Malignant Hyperthermia
In several porcine breeds that exhibited inheritance of malignant hyperthermia (145600), Otsu et al. (1991) and Fujii et al. (1991) identified a mutation in the Ryr1 gene (R615C). In 1 of 35 Canadian families with malignant hyperthermia, Gillard et al. (1991) identified the same mutation, which is R614C (180901.0001) in humans.
In patients with malignant hyperthermia, Manning et al. (1998) identified 4 adjacent mutations in the RYR1 gene: R2163C (180901.0010), R2163H (180901.0011), V2168M (180901.0013), and T2206M (180901.0014).
Brandt et al. (1999) stated that 21 RYR1 mutations had been identified in families with malignant hyperthermia, 4 of which were also associated with central core myopathy. By screening for these 21 mutations in 105 MH families, including 10 families with central core disease (CCD) (CMYO1A; 117000), phenotyped by the IVCT according to the European protocol, the authors determined the approximate mutation frequencies, with R614C (9%; 180901.0001) and G2434R (7%; 180901.0007) being the most common mutations. Brandt et al. (1999) also detected 2 novel mutations, each in a single pedigree. In the 109 individuals of the 25 families with RYR1 mutations, cosegregation between genetic result and IVCT was almost perfect. Only 3 genotypes were discordant with the IVCT phenotypes, suggesting a true sensitivity of 98.5% and a specificity of minimally 81.8% for this test. Screening of the transmembrane region of RYR1 did not yield a new mutation, confirming the cytosolic portion of the protein to be of main functional importance for pathogenesis.
Sambuughin et al. (2001) reported that malignant hyperthermia susceptibility (MHS) had been found to be associated with 30 different mutations in the RYR1 gene, all of which represent single-nucleotide changes.
Monnier et al. (2005) reported the results of correlation studies performed with molecular, pharmacologic, histologic, and functional data obtained from 176 families, 129 referred to as 'confirmed' and 46 as 'potential' MHS families. Extensive molecular analysis allowed them to identify a variant in 60% of the confirmed MHS families and resulted in the characterization of 11 new variants in the RYR1 gene. Most of the mutations clustered in the MH1 (52%) and MH2 (36%) domains of the RYR1 gene.
Johnston et al. (2021) reported an adaptation of the American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) pathogenicity criteria by a variant curation expert panel for the classification of RYR1 variants in malignant hyperthermia susceptibility. Using the new criteria, 44 RYR1 gene mutations previously determined to be diagnostic by the European Malignant Hyperthermia Group (EMHG) were categorized: 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of unknown significance. Johnston et al. (2021) concluded that use of the new criteria should allow for more consistent classification of RYR1 mutations.
Autosomal Dominant Congenital Myopathy 1A With Susceptibility to Malignant Hyperthermia
In affected members of a large multigenerational Canadian family with autosomal dominant congenital myopathy-1A (CMYO1A; 117000) with central core disease on skeletal muscle biopsy (CCD) and susceptibility to malignant hyperthermia originally reported by Shuaib et al. (1987), Zhang et al. (1993) identified a heterozygous missense mutation in the RYR1 gene (R2435H; 180901.0003).
In 2 Italian brothers (family 4T) with CMYO1A manifest as central core disease (CCD) on skeletal muscle biopsy, Quane et al. (1993) identified a heterozygous missense mutation in the RYR1 gene (I403M; 180901.0005). The clinically unaffected father also carried the mutation; he did not undergo muscle biopsy. In 4 members of another Italian family (2T) with variable expression of CMYO1A and malignant hyperthermia, Quane et al. (1993) identified a heterozygous mutation in the RYR1 gene (R163C; 180901.0004). Of note, Quane et al. (1993) also identified the R163C mutation in a Danish family (D15) in which a mother and her 2 children had MHS without clinical signs of a myopathy and absence of cores on muscle biopsy. These findings demonstrated phenotypic variability, both within families and between families with the same mutation.
Lynch et al. (1999) studied a large Mexican kindred in which all affected members had a clinically severe and highly penetrant form of CMYO1A. Sequencing of the entire RYR1 cDNA in an affected member identified a single heterozygous mutation in the C-terminal transmembrane/luminal domain of the protein (180901.0012). The introduction of this mutation into a recombinant RyR1 protein expressed in HEK293 cells resulted in loss of channel activation by caffeine and halothane and a significant reduction in ryanodine binding. These and additional findings, which pointed to a high basal activity of the mutant Ca(2+) channel, could explain the muscle weakness and muscle atrophy observed in CCD patients in this family.
Scacheri et al. (2000) identified a heterozygous mutation in the RYR1 gene (180901.0030) in affected members of a large family with CMYO1A. Skeletal muscle biopsies from 2 affected individuals showed the presence of central cores in over 85% of myofibers and nemaline rods in 5 to 25% of myofibers. Scacheri et al. (2000) suggested that nemaline bodies may be a secondary feature in this disorder.
In 5 members of a French family with CMYO1A, Monnier et al. (2000) identified a heterozygous missense mutation in the RYR1 gene (Y4796C; 180901.0016). The mutation occurs in the C-terminal channel-forming domain of the RYR1 protein. Expression of the mutant RYR1 cDNA in rabbit HEK293 cells produced channels with increased caffeine sensitivity, cells with increased resting cytoplasmic Ca(2+) levels, and a significantly reduced maximal level of Ca(2+) release, suggesting an increased rate of Ca(2+) leakage in the mutant channel. The authors hypothesized that the resulting chronic elevation in myoplasmic Ca(2+) concentration may be responsible for the severe phenotype in this family. Haplotype analysis indicated that the mutation arose de novo in the proband.
In affected members of 16 unrelated families with CMYO1A, Monnier et al. (2001) identified 12 different missense mutations in the C-terminal domain of RYR1 (see, e.g., I4898T, 180901.0012; V2168M, 180901.0013; a 9-bp del, 180901.0018; R4861H, 180901.0019; and R4893W, 180901.0044). Since the muscle symptoms in the families suggested a defect in Ca(2+) homeostasis, the authors sequenced exons in the C-terminal channel-forming domain of RYR1, which is involved in Ca(2+) movement. V2168M occurred in exon 39, but all of the other mutations occurred in exons 91 through 102. Four de novo mutations were found, indicating that de novo mutations in RYR1 are not rare and may confound genetic studies of families that present with congenital myopathies. Functional studies of the mutations were not performed. Molecular modeling based on a 4-transmembrane domain model suggested that the mutations concentrated mostly in the myoplasmic and luminal loops linking, respectively, transmembrane domains T1 and T2 or T3 and T4 of RYR1 and may therefore affect the excitation-contraction process in skeletal muscle. The patients were ascertained from a cohort of 34 families with congenital myopathy associated with central cores on muscle biopsy who underwent genetic analysis; RYR1 mutations were found in 47% of families.
Tilgen et al. (2001) screened the C-terminal domain of the RYR1 gene for mutations in 50 European patients diagnosed clinically and/or histologically as having congenital myopathy with central cores on biopsy (central core disease, CCD). Four novel missense mutations (see, e.g., 180901.0012 and 180901.0019) were identified in 13 of 25 index patients. The mutations clustered in exons 101 and 102 and replaced conserved amino acids. Lymphoblasts derived from patients carrying these C-terminal RYR1 mutations exhibited a release of calcium from intracellular stores in the absence of any pharmacologic activators of RYR; significantly smaller thapsigargin-sensitive intracellular calcium stores, compared to lymphoblasts from control individuals; and a normal sensitivity of the calcium release to the RYR inhibitor dantrolene. The authors suggested that the C-terminal domain of RYR1 may be a hotspot for mutations leading to the CCD phenotype.
Zorzato et al. (2003) identified a patient with severe CCD and her mother with mild CCD who were both heterozygous for a deletion (amino acids 4863-4869; 180901.0024) in the pore-forming region of the sarcoplasmic reticulum calcium release channel. The deleted amino acids form part of the luminal loop connecting membrane-spanning segments M8 and M10 and are conserved in all known vertebrate RYR1 isoforms. Lymphoblastoid cells carrying the RYR1 deletion exhibited an 'unprompted' calcium release from intracellular stores, resulting in significantly smaller thapsigargin-sensitive intracellular Ca(2+) stores compared with lymphoblastoid cells from controls. Blocking the RYR1 with dantrolene restored the intracellular calcium stores to levels similar to those found in controls. Single-channel and [3H]ryanodine-binding measurements in HEK293 cells heterologously expressing mutant channels revealed a reduced ion conductance and loss of ryanodine binding and regulation by Ca(2+).
In 11 patients from 4 unrelated families with CMYO1A, Quinlivan et al. (2003) identified heterozygous mutations in the RYR1 gene (see, e.g., R4861H, 180901.0019; R4893W, 180901.0044; and Y4864C, 180901.0045). All mutations occurred in region 3 of the RYR1 gene. The mutation was inherited in an autosomal dominant pattern in 3 families (families A, B, and C), whereas the mutation occurred de novo in the proband from family D.
In 4 unrelated Japanese patients with CMYO1A and a pathologic diagnosis of congenital neuromuscular disease with uniform type 1 fiber (CNMDU1), Sato et al. (2008) identified heterozygous mutations in the RYR1 gene (see, e.g., 180901.0019; 180901.0033-180901.0034). The father of 1 patient had the same mutation as his son (180901.0033) and was diagnosed with CCD (Wu et al., 2006; Tojo et al., 2000), indicating that RYR1 mutations can cause variable findings on skeletal muscle biopsy.
Autosomal Recessive Congenital Myopathy 1B
In affected members of a consanguineous Algerian family with autosomal recessive congenital myopathy-1B (CMYO1B; 255320) characterized by the presence of multiple, short-length core lesions (minicores) on skeletal muscle biopsy, Ferreiro et al. (2002) identified a homozygous missense mutation in the RYR1 gene (P3527S; 180901.0021). Three children in the family presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle, and hands, joint hyperlaxity, and multiple minicores on skeletal muscle biopsy. New muscle biopsies from the 3 patients in adulthood demonstrated central core disease with rods; no cores were found in the healthy parents.
In a 19-year-old girl, born of consanguineous parents (family 1), with CMYO1B, Jungbluth et al. (2002) identified a homozygous missense mutation in the RYR1 gene (V4849I; 180901.0022). In a 9-year-old girl, born of consanguineous parents, with autosomal recessive CMYO1B and central core disease on muscle biopsy, Kossugue et al. (2007) identified a homozygous V4849I substitution in the RYR1 gene.
Monnier et al. (2003) and Jungbluth et al. (2005) identified biallelic mutations in the RYR1 gene (see, e.g., 180901.0025-180901.0029) in patients with CMYO1B manifest as minicore myopathy with external ophthalmoplegia.
Monnier et al. (2008) reported a 9-year-old Dutch boy with a severe autosomal recessive myopathy with ptosis and facial diplegia associated with compound heterozygous mutations in the RYR1 gene: V4849I and a 4-bp insertion (180901.0032). Monnier et al. (2008) postulated that since the patient had a hypomorphic frameshift RYR1 allele, the resultant phenotype was more severe compared to those patients with homozygous V4849I mutations.
In 17 patients, all from unrelated nonconsanguineous families, with CMYO1B and a clinicopathologic diagnosis of centronuclear myopathy (CNM), Wilmshurst et al. (2010) identified mutations in the RYR1 gene (see, e.g., 180901.0035-180901.0037). Compound heterozygosity for a nonsense and missense mutation was found in all except 3 patients, in whom a second pathogenic allele could not be found. The phenotype was characterized by onset at birth, neonatal hypotonia and weakness, delayed motor development, external ophthalmoplegia, and bulbar involvement. In addition to central nuclei, prominent histopathologic findings included multiple internalized nuclei, type 1 fiber predominance and hypotrophy, relative type 2 hypertrophy, and oxidative abnormalities in electron microscopic analysis, although frank cores were not typically seen. Twelve of the patients were from South Africa, and haplotype analysis suggested founder effects for some of the mutant alleles. The 17 patients were ascertained from a larger group of 24 patients with a diagnosis of CNM, indicating that RYR1 mutations can account for this subtype of myopathy. Wilmshurst et al. (2010) postulated that disorder resulted from disturbed assembly and/or malfunction of the excitation-contraction machinery.
In 3 (8.3%) of 36 families with CMYO1B manifest as fetal akinesia deformation/lethal pterygium syndrome, McKie et al. (2014) identified 3 different homozygous nonsense or intragenic deletion mutations in the RYR1 gene (180901.0039-180901.0041). McKie et al. (2014) suggested that RYR1 mutation analysis should be performed in cases with severe early lethal fetal akinesia even in the absence of specific histopathologic indicators of RYR1-related disease.
King-Denborough Syndrome
In a patient with King-Denborough syndrome (KDS; 619542), D'Arcy et al. (2008) identified a heterozygous mutation in the RYR1 gene (180902.0038).
By direct RYR1 sequencing, Dowling et al. (2011) identified heterozygous missense mutations in 4 patients with KDS, a 6-year-old boy (T2203M; 180901.0014) and 3 members of 1 family (R2452W; 180901.0042). In a patient with severe kyphoscoliosis, moderate proximal weakness, and distal joint laxity, Dowling et al. (2011) identified heterozygosity for an S2776F mutation in the RYR1 gene; however, her father, who also had the mutation, was asymptomatic. Dowling et al. (2011) concluded that the S2776F mutation was probably pathogenic but not sufficient to cause the patient's phenotype.
In a 2-year-old boy with KDS, Joseph et al. (2017) identified a heterozygous missense mutation in the RYR1 gene (R2508C; 180901.0043). Functional studies were not performed.
Manning et al. (1998) tabulated the 17 mutations that had been identified in the RYR1 gene in families with MHS and CCD. They estimated that the 4 novel mutations they found accounted for approximately 11% of MH cases. The 13 that had been identified before their study were located in 2 regions, the N-terminal and central regions. Their study and that of others indicated that the gene segment 6400-6700 is a mutation hotspot. Two different amino acid substitutions had been identified in each of 3 codons: 614, 2163, and 2458. Correlation analysis of IVCT data available for pedigrees bearing these 17 RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. The findings indicated that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic, and suggested a link between the caffeine threshold and tension values and the MH/CCD phenotype.
McCarthy et al. (2000) noted that the majority of RYR1 mutations appeared to be clustered in the N-terminal amino acid residues 35-614 (referred to as the MH/CCD region-1) and the centrally located residues 2163-2458 (MH/CCD region-2). The only mutation identified outside of these regions was a single mutation associated with a severe form of CCD in the highly conserved C terminus of the gene, I4898T (180901.0012). All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C terminus, which resides in the luminal/transmembrane region. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis.
Robinson et al. (2002) stated that 15 RYR1 N-terminal mutations are considered causative of MHS, and that 5 of these are also associated with CCD. In an extensive U.K. population survey, they detected 8 of these 15 mutations in 85 of 297 (29%) unrelated MH susceptibility cases, with G2434R (180901.0007) detected in 53 cases (18%). R163C (180901.0004), R2163H (180901.0011), and R2435H (180901.0003), RYR1 mutations associated with both CCD and MH, had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the N terminus (R163C; G341R, 180901.0006) had a relatively greater effect on response to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in 7 families (9 individuals), with 5 false-positives and 4 false-negatives. The clinical and genetic data in this study demonstrated that RYR1 mutations involved in CCD are those associated with 1 end of the spectrum of MH IVCT phenotypes.
Ducreux et al. (2004) found that cultured human myotubes with the I4898T mutation in the RYR1 gene (180901.0012), which is in the C-terminal hydrophobic membrane-spanning region of the protein and causes CCD, had a 4-fold increase in background levels of IL6 in the absence of RYR1 activation compared to controls; cells with the V2168M (180901.0013) mutation, which causes MHS, had background IL6 levels similar to control cells. In addition, cells with the CCD mutation had significantly less agonist-induced calcium release from intracellular stores compared to control cells or MHS cells. The findings indicated that mutations in the C-terminal domain reduce the amount of calcium released via the RYR1 channel, resulting in altered excitation-contraction coupling. Release of IL6, an inflammatory and pyrogenic cytokine, may affect signaling pathways responsible for muscle fiber abnormalities in CCD.
Lyfenko et al. (2004) reviewed the dynamic alterations in myoplasmic calcium metabolism in disorders caused by mutation in the RYR1 gene, and discussed molecular mechanisms by which these genetic defects lead to distinct clinical and histopathologic manifestations. Benkusky et al. (2004) reviewed RYR1 and RYR2 mutations and their role in muscle and heart disease, respectively.
Klein et al. (2012) noted that dominant mutations involved in congenital myopathy-1A (CMYO1A; 117000) are mostly confined to the C-terminal region of the gene, particularly region 3, whereas mutations involved in MHS are mostly detected in regions 1 and 2 within the N terminal. Most dominant mutations are missense.
McCarthy et al. (2000) pointed out that the RYR1 G341R mutation (180901.0006) is present in about 6% of Irish/English/French families, but is rare in northern Europe. The R614C mutation (180901.0001) is more common in German families (9%), while the V2168M (180901.0013) mutation is common in Swiss families but relatively rare otherwise.
Monnier et al. (2005) found that the RYR1 R614C mutation is the most prevalent mutation in French families with MHS, whereas it is poorly represented in affected families from the U.K. In contrast, the G2434R (180901.0007) and V2168M (180901.0013) mutations, which are the most prevalent in MHS families from the U.K. (Robinson et al., 2002) and Switzerland (Girard et al., 2001), respectively, are present at a much lower level in affected French families.
In several porcine breeds exhibiting inheritance of malignant hyperthermia, Otsu et al. (1991) and Fujii et al. (1991) identified a 1843C-T transition in the RYR1 gene, resulting in an arg615-to-cys (R615C) substitution. The same mutation was found in 5 major breeds (see Harbitz et al. (1992) for a sixth) of lean, heavily muscled swine, and haplotyping suggested that the mutation in all had a common origin, demonstrating a founder effect in these animals. Fujii et al. (1991) suggested that the mutation had been selected for by breeders because it was associated with lean and heavy muscles. The porcine R615C mutation corresponds to the R614C mutation identified in humans with malignant hyperthermia (180901.0001).
Takeshima et al. (1994) developed mice with a targeted mutation in the Ryr1 gene. Homozygous mice died perinatally with gross abnormalities of skeletal muscle. The contractile response to electrical stimulation under physiologic conditions was totally abolished in mutant embryonic muscle. However, ryanodine receptors other than Ryr1 seemed to exist, because a response to caffeine was retained. Takeshima et al. (1994) concluded that RYR1 is essential for both muscular maturation and excitation-contraction coupling and that RYR1 function during excitation-contraction coupling cannot be substituted by other receptor subtypes.
Takeshima et al. (1995) demonstrated that the residual caffeine-activated calcium release in Ryr1 null mice is likely mediated by Ryr3 (180903).
Barone et al. (1998) generated double mutant mice carrying a targeted disruption of both the Ryr1 and the Ryr3 (180903) genes. Skeletal muscles from mice homozygous for both mutations did not contract in response to caffeine or ryanodine. In addition, these muscles showed very low tension when directly activated with micromolar ionized calcium after membrane permeabilization, indicating either poor development or degeneration of the myofibrils. This was confirmed by biochemical analysis of contractile proteins. Electron microscopy confirmed small size of myofibrils and showed complete absence of ryanodine receptors in the junctional sarcoplasmic reticulum.
Chelu et al. (2006) found that mice with a homozygous for the Y522S (180901.0031) mutation in the Ryr1 gene exhibited skeletal defects and died during embryonic development or soon after birth. Heterozygous mice, corresponding to the human occurrence of this mutation, were susceptible to malignant hyperthermia and showed whole body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Skeletal muscles from heterozygous mice exhibit increased susceptibility to caffeine- and heat-induced contractures in vitro. In addition, the heterozygous expression of the mutation resulted in enhanced RyR1 sensitivity to activation by temperature, caffeine, and voltage but not uncompensated sarcoplasmic reticulum calcium leak or store depletion.
Durham et al. (2008) found that skeletal muscle from heterozygous Y522S-mutant mice displayed increased basal oxidative stress with increased levels of reactive oxygen and nitrogen species compared to wildtype mice. Further studies suggested that the reactive species resulted from increased calcium release from the leaky mutant RyR1 channel in resting muscles. Increased calcium combined with increased reactive nitrogen species produced S-nitrosylation of the mutant leaky channel that further enhanced channel activity at increased temperatures. Durham et al. (2008) postulated a destructive feed-forward cycle of increased calcium release, increased temperature-sensitivity of the mutant channel, and increased muscle contraction with elevated temperature and heat stress. Over time, this cycle induced a myopathy characterized by damaged mitochondria and decreased force generation.
Bellinger et al. (2009) found that the Ryr1 channel in skeletal muscle from the mdx mouse, a model of Duchenne muscular dystrophy (DMD; 310200) with disruption of the dystrophin gene (DMD; 300377), showed increased inducible nitric oxide (NOS2A; 163730)-mediated S-nitrosylation of cysteine residues, which depleted the channel complex of calstabin-1 (FKBP12; 186945). This resulted in leaky channels with increased calcium flux. These changes were age-dependent and coincided with dystrophic changes in muscle. Prevention of calstabin-1 depletion from Ryr1 with S107, a compound that binds the Ryr1 channel and enhances binding affinity, inhibited sarcoplasmic reticulum calcium leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function, and increased exercise performance in mdx mice. Bellinger et al. (2009) proposed that the increased calcium flux via a defective Ryr1 channel contributes to muscle weakness and degeneration in DMD by increasing calcium-activated proteases.
To understand the skeletal muscle pathology in patients with an RYR1 mutation that results in decreased RYR1 protein content (e.g., Q1979X), Elbaz et al. (2019) generated a mouse model with a heterozygous mutation in exon 36 (Gln1970fsTer16) of the Ryr1 gene. Mice heterozygous for the mutation had lower running distance before and after exercise training, and lower median cruise speed, compared to wildtype littermates. Ryr1 protein content was lower in mutant mice compared to wildtype in the extensor digitorum longus (EDL) (37.6% of wildtype) and soleus muscles (58.7% of wildtype), and gene transcript levels were 50% of wildtype levels. Electron microscopy studies in EDL muscles from mutant mice showed an uneven distribution and abnormal morphology of calcium release units (CRUs), including an increase of CRUs with only 2 elements, suggesting a reduction in the number of calcium release sites. Functional studies showed that muscle strength and depolarization-induced calcium transients were reduced in mutant mice, at 20% and 15% of wildtype, respectively. Because the level of Ryr1 protein content was quantitatively more abnormal than strength and peak calcium transient deficiencies in the mutant mice, Elbaz et al. (2019) suggested that there may be an adaptation to chronic Ryr1 protein deficiency.
Elbaz et al. (2019) generated a mouse model with compound heterozygous mutations in RYR1, Q1970fsX16 in exon 36 and A4329D in exon 91, which are isogenic to the RYR1 mutations identified in a severely affected child with autosomal recessive multiminicore disease (see 255320). Both Ryr1 protein and transcript levels were reduced in muscle from the mutant mice, and Hdac4 protein (605314) was found to be upregulated. Compared to their wildtype littermates, mutant mice had lower body weight at age 18 weeks, and lower spontaneous running distance and cruising speed at age 3 months. Histologic examination of mutant muscles showed regions of severe myofibrillar disorganization as well as reduced numbers of calcium release units (CRUs) and mitochondria. Functional testing showed that the mutant muscles developed less isometric force and had smaller evoked calcium transients. Elbaz et al. (2019) concluded that the mutant mice recapitulated the clinical features seen in patients with multiminicore disease and provided insight into the pathologic mechanism of the disease.
Brennan et al. (2019) generated a compound heterozygous mouse model of RYR1-related myopathy (RYR1-RM) in which one allele of Ryr1 had a thr4709-to-met (T4709M) mutation, equivalent to human T4706M, and the other allele had a 16-bp frameshift deletion in exon 96. Mutant mice were born at the expected mendelian frequency, although a small number died during the first 3 days of life. Mutant mice that survived beyond 3 days exhibited reduced body weight due to a substantial reduction of the myofiber compartment. The disease progressed rapidly, with most mice dying before 57 days of age due to respiratory failure caused by spine changes and muscle weakness. Mutant mice exhibited reduced muscle force generation, and mutant muscles had decreased myofiber size but preserved muscle structure. Levels of Ryr1 and Dhpr (QDPR; 612676) proteins were reduced in mutant muscles, and combined with reduced muscle force generation, this reduction led to aberrant intracellular calcium dynamics in mutant mice. Knockin mice homozygous for the T4709M mutation displayed a potentially lethal hyperthermic response during isoflurane exposure, recapitulating the enhanced sensitivity to volatile anesthetics seen in RYR1-RM patients with malignant hyperthermia.
In 3 members of 1 of 35 Canadian families with malignant hyperthermia (MHS1; 145600), Gillard et al. (1991) identified a heterozygous c.1840C-T transition in the RYR1 gene, resulting in an arg614-to-cys (R614C) substitution, which is comparable to the R615C mutation found in pigs with malignant hyperthermia (see ANIMAL MODEL). Of the mutation carriers, the proband experienced an episode of malignant hyperthermia during surgery, and the other 2 (her mother and sister) had positive muscle biopsy contracture tests. The proband's father and brother, who did not carry the mutation, had negative contracture tests.
Hall-Curran et al. (1993) did not identify the R614C mutation in in 100 British families with malignant hyperthermia, suggesting that the prevalence of this mutation is less than 3% in the U.K. population. The authors concluded that presymptomatic testing for R614C, as suggested by Otsu et al. (1992), would have no practicality in the British population.
In a German family with MHS, Deufel et al. (1995) identified the R614C mutation in homozygosity or heterozygosity in affected individuals. In vitro contracture test (IVCT) phenotypes were similar between heterozygotes and 1 homozygous individual (408). The mutation was present on 2 different haplotypes in the family. In addition, 3 individuals with MHS in a different branch of the family did not carry the R614C mutation; IVCT results for these affected individuals did not differ from those carrying the R614C mutation. The authors suggested that the results may challenge the causative role of the mutation and possibly the role of the RYR1 gene itself in human malignant hyperthermia susceptibility, at least in some cases.
Fagerlund et al. (1994, 1995) found the R614C mutation in 3 of 41 Swedish families with MHS, but in none of 48 Danish families.
Fagerlund et al. (1997) reported 2 families in which there was recombination between MH susceptibility and the R614C mutation, in 1 and 3 individuals, respectively. They suggested that these findings make it necessary to reconsider the specificity of the in vitro contracture test (IVCT) and/or the role of R614C as a cause of MH susceptibility in some families exhibiting this mutation.
Variant Function
Otsu et al. (1994) designed experiments to demonstrate physiologically that the R614C mutation alters ryanodine receptor function. They estimated cytoplasmic calcium ion responses to halothane and caffeine in myoblastic cells expressing the normal or mutant ryanodine receptor by transfecting the corresponding cDNAs. Exposure to clinical doses of halothane resulted in a rapid increase in calcium ion in cells expressing the mutant receptor, whereas no calcium changes were observed in cells expressing the wildtype receptor.
In 2 sibs (TJ and SJ, family 39) with malignant hyperthermia (MHS1; 145600), Gillard et al. (1992) identified a heterozygous G-to-A transition in the RYR1 gene that resulted in a gly248-to-arg (G248R) substitution. The mutation was identified by PCR amplification followed by direct sequencing. The proband, TJ, experienced an episode of malignant hyperthermia while undergoing tonsillectomy, and also had muscle cramps.
In affected members of a large Canadian family with congenital myopathy-1A (CMYO1A; 117000) manifest as central core disease on skeletal muscle biopsy, Zhang et al. (1993) identified a heterozygous c.7301G-A transition in the RYR1 gene, resulting in an arg2434-to-his (ARG2434HIS) substitution. This appeared to be a 'private' mutation since it was restricted to this single large family among more than 100 Canadian CCD and MHS families tested. Some members of the family had previously been reported by Shuaib et al. (1987) as having mild myopathy, central cores on muscle biopsy, and susceptibility to malignant hyperthermia.
Richter et al. (1997) referred to this mutation as arg2435-to- his (R2435H), according to the revised numbering of amino acids based on the corrected sequence data of Phillips et al. (1996).
In affected members of 2 unrelated families (2T and D15) with susceptibility to malignant hyperthermia (MHS1; 145600), Quane et al. (1993) identified heterozygosity for a c.487C-T transition in the RYR1 gene that resulted in an arg163-to-cys (R163C) substitution. In family 2T, some persons also had manifestations of a congenital myopathy (CMYO1A; 117000) with central cores on skeletal muscle biopsy.
O'Brien et al. (1995) reported a family in which 2 members diagnosed with MHS by means of the in vitro contracture test were found to be heterozygous for the R163C mutation, but 2 other members diagnosed with MHS on the same basis did not have the mutation. Reference was made to other families in which the major phenotype did not cosegregate with the arg614-to-cys (R614C; 180901.0001) or the gly341-to-arg (G341R; 180901.0006) mutations.
Fagerlund et al. (1994, 1995) found the heterozygous R163C mutation in 1 of 48 Danish families with MHS, but in none of 41 Swedish families.
Tobin et al. (2001) identified a heterozygous R163C mutation in a 12-year-old boy with MHS. The patient's father also carried the mutation. The boy experienced an episode of MH during surgery for reduction of a humerus fracture, from which he recovered; he died 8 months later after participation in a football game when the ambient temperature was approximately 80 degrees F, with apparent heat stroke (rectal temperature greater than 108 degrees F).
In 2 affected brothers from an Italian family (4T) with congenital myopathy-1A (CMYO1A; 117000) and central cores on skeletal muscle biopsy, Quane et al. (1993) demonstrated heterozygosity for a c.1209C-G transversion in the RYR1 gene that resulted in an ile403-to-met substitution (I403M). The sibs inherited the mutation from their clinically normal father, who was not available for biopsy.
In affected individuals from 3 unrelated families with malignant hyperthermia susceptibility (MHS1; 145600), Quane et al. (1994) identified a heterozygous c.1021G-A transition in the RYR1 gene, resulting in a gly341-to-arg (G341R) substitution. The authors suggested that the G341R mutation may be responsible for approximately 10% of all MHS cases in Caucasians. However, Fagerlund et al. (1996) discovered this mutation in only 1 of 89 Swedish and Danish families with MHS.
Alestrom et al. (1995) used the amplification-created restriction sites (ACRS) technique to detect the G341R mutation. The method discriminated quickly and efficiently between homozygotes with the mutation, heterozygotes, and homozygotes without the mutation.
Adeokun et al. (1997) reported a large family in which the G341R mutation did not show complete cosegregation with MHS: it occurred in only 7 of 12 individuals in the kinship demonstrated to be MH sensitive by in vitro contracture tests (IVCTs), and susceptibility was inherited from parents who were homozygous wildtype c.1021G, as well as from parents who were heterozygotes.
Monsieurs et al. (1998) found that 9 of 13 carriers of the G341R mutation in 2 families had elevated serum creatine kinase levels (up to 6 times the upper limit of normal). All had normal neurologic exams and muscle histology. The third family did not show increased creatine kinase levels. The authors suggested that the G341R mutation may be a cause of chronic elevation of serum creatine kinase in asymptomatic individuals.
Whereas the G341R mutation is a frequent cause of malignant hyperthermia in European populations, Stewart et al. (1998) did not find the mutation in 114 North American individuals screened because of a family history or personal history of malignant hyperthermia.
In affected individuals from 4 of 104 unrelated families with malignant hyperthermia susceptibility (MHS1; 145600), Keating et al. (1994) identified a heterozygous gly2433-to-arg (GLY2433ARG) change in the RYR1 gene resulting from a c.7297G-A transition. The authors noted that this mutation is adjacent to the R2434H mutation (180901.0003), which may indicate a second cluster in the RYR1 gene where MHS and/or central core disease (CMYO1A; 117000) mutations occur.
In the numbering system of amino acids provided by the corrected sequence data for human RYR1 according to Phillips et al. (1996), this mutation was referred to as G2434R by Richter et al. (1997). Functional studies showed that the G2434R mutation enhanced the sensitivity of RYR1 to activating concentrations of calcium and to caffeine. In parallel, the sensitivity to inhibiting concentrations of calcium and calmodulin was reduced, transferring the mutant calcium-release channel into a hyperexcitable state.
In families with malignant hyperthermia susceptibility (MHS1; 145600), Manning et al. (1998) reported 2 novel mutations in the RYR1 gene: a heterozygous c.7372C-T transition, resulting in an arg2458-to-cys (R2458C) substitution, and a heterozygous c.7373G-A transition, resulting in an arg2458-to-his (R2458H; 180901.0009) substitution. Both changes occurred at a CpG dinucleotide in the central region of the RYR1 gene. The R2458C mutation was observed in a Swiss pedigree and in an Italian pedigree; the R2458H mutation was found in a French pedigree. Both mutations segregated with the malignant hyperthermia susceptibility phenotype or the MH equivocal (MHE) phenotype. The authors noted that these mutations represented the most C-terminal mutations in the RYR1 gene reported to that time.
See 180901.0008 and Manning et al. (1998).
In 2 unrelated families (D1 and D2), Manning et al. (1998) demonstrated that members with malignant hyperthermia (MHS1; 145600) had a heterozygous c.6487C-T transition in the RYR1 gene, resulting in an arg2163-to-cys (R2163C) substitution.
In an Italian mother and daughter (family It2) with MHS (145600), Manning et al. (1998) identified a heterozygous c.6488G-A transition in the RYR1 gene, resulting in an arg2163-to-cys (R2163C) substitution. The family had been studied by Tegazzin et al. (1994). The proband had undergone 8 previous surgical procedures under general anesthesia before presenting with an MH crisis. On 6 of these previous occasions, an MH-triggering anesthetic had been used. Histologic examination of muscle biopsy from the mother revealed a predominance of type 1 fibers with central cores present in many fibers. Neither she nor her daughter had symptoms of a congenital myopathy.
In a large Mexican kindred in which affected members through 4 generations had autosomal dominant congenital myopathy-1A (CMYO1A; 117000) associated with central cores on muscle biopsy, Lynch et al. (1999) identified a heterozygous c.14693T-C transition in the RYR1 gene, resulting in an ile4898-to-thr (I4898T) mutation in the C-terminal transmembrane region of the RYR1 protein. In 2 family members tested, malignant hyperthermia was also present. Lynch et al. (1999) noted that all previously reported RYR1 mutations had been located either in the cytoplasmic N terminus or in a central cytoplasmic region of the protein. Introduction of the I4898T mutation into a rabbit RYR1 cDNA and expression in HEK293 cells resulted in abolition of response to the agonists halothane and caffeine. Coexpression of normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RYR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca(2+) release were reduced by 67%. Binding of [3H]ryanodine indicated that the heterozygous channel was activated by Ca(2+) concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells showed a significantly increased resting cytoplasmic Ca(2+) level and a significantly reduced luminal Ca(2+) level. These data indicated a leaky channel, possibly caused by a reduction in the Ca(2+) concentration required for channel activation. Comparison with 2 other coexpressed mutant/normal channels suggested that the I4898T mutation produces one of the most abnormal RYR1 channels that had been investigated, and this level of abnormality was reflected in the severe and penetrant phenotype of the patients with congenital myopathy in the pedigree.
Tilgen et al. (2001) identified the I4898T mutation, resulting from a c.14693T-C transition, in 3 of 25 unrelated individuals with CMYO1A. The isoleucine residue is highly conserved and is located in the C-terminal hydrophobic membrane-spanning region of the protein.
In 2 members of a family (CCD05) and an unrelated patient (CCD11) with CMYO1A, Monnier et al. (2001) identified a heterozygous I4898T mutation in exon 102 of the RYR1 gene.
Variant Function
Avila et al. (2001) expressed the analogous rabbit mutation (I4897T) in skeletal myotubes derived from Ryr1-knockout mice. They found that homozygous expression of I4897T in myotubes resulted in a complete uncoupling of sarcolemmal excitation from voltage-gated sarcoplasmic reticulum (SR) calcium ion release without significantly altering resting cytosolic calcium ion levels, sarcoplasmic reticulum calcium ion content, or Ryr1-mediated enhancement of dihydropyridine receptor (DHPR) channel activity. Coexpression of both I4897T and wildtype Ryr1 resulted in a 60% reduction in voltage-gated SR calcium ion release, again without altering resting cytosolic calcium ion levels, SR calcium ion content, or DHPR channel activity. These findings indicated that muscle weakness in patients with the I4898T mutation involves a functional uncoupling of sarcolemmal excitation from SR calcium ion release, rather than the expression of overactive or leaky SR calcium ion release channels.
In affected individuals from 8 Swiss families with malignant hyperthermia (MHS1; 145600), Manning et al. (1998) identified a heterozygous G-to-A change in the RYR1 gene, resulting in a val2168-to-met (V2168M) substitution.
Monnier et al. (2001) identified a heterozygous V2168M mutation resulting from a c.6502G-A transition in exon 39 of the RYR1 gene in a 52-year-old patient (CCD14) with congenital myopathy-1A (CMYO1A; 117000). She had a history of mild orthopedic problems during infancy, mild proximal muscle weakness, and cores on muscle biopsy.
Malignant Hyperthermia, Susceptibility to, 1
In affected members of a family with malignant hyperthermia (MHS1; 145600), Manning et al. (1998) identified a heterozygous c.6617C-T transition in the RYR1 gene, resulting in a thr2206-to-met (T2206M) substitution.
Wehner et al. (2002) identified the T2206M mutation in patients with MHS. Myotubes derived from individuals with the T2206M mutation had an abnormal response of the intracellular calcium concentration to 4-chloro-m-cresol and to caffeine. In myotubes, the EC50 for 4-chloro-m-cresol and for caffeine was reduced strikingly, indicating that this mutation is pathogenic for malignant hyperthermia.
King-Denborough Syndrome
In a 6-year-old boy (patient 1) with King-Denborough syndrome (KDS; 619542), Dowling et al. (2011) identified heterozygosity for the c.6617C-T transition in exon 40 of the RYR1 gene, resulting in a T2206M substitution. The mutation was identified by RYR1 gene sequencing. Western blot analysis in patient muscle tissue showed an 84% reduction in RyR1 protein level compared to control.
Brown et al. (2000) reported a large Maori pedigree consisting of 5 probands who experienced clinical episodes of malignant hyperthermia (MHS1; 145600) and 130 members diagnosed by in vitro contracture testing (IVCT). Sequencing of RYR1 cDNA in an affected individual from this pedigree identified a novel heterozygous c.14477C-T transition, resulting in a thr4826-to-ile (T4826I) substitution in the C-terminal region/transmembrane loop of the skeletal muscle ryanodine receptor. This was the first mutation in the RYR1 C-terminal region associated solely with MHS.
In 5 affected members of a 3-generation French family with congenital myopathy-1A (CMYO1A; 117000), Monnier et al. (2000) identified a heterozygous c.14387G-A transition in exon 100 of the RYR1 gene, resulting in a tyr4796-to-cys (Y4796C) substitution in the C-terminal channel-forming domain of the RYR1 protein. Expression of the mutant RYR1 cDNA in rabbit HEK293 cells produced channels with increased caffeine sensitivity, cells with increased resting cytoplasmic Ca(2+) levels, and a significantly reduced maximal level of Ca(2+) release, suggesting an increased rate of Ca(2+) leakage in the mutant channel. The authors hypothesized that the resulting chronic elevation in myoplasmic Ca(2+) concentration may be responsible for the severe phenotype in this family. Haplotype analysis indicated that the mutation arose de novo in the proband. Testing of skeletal muscle from the proband showed susceptibility to malignant hyperthermia.
In affected members of 2 unrelated families with malignant hyperthermia (MHS1; 145600), Sambuughin et al. (2001) identified a heterozygous 3-bp deletion (GGA) in exon 44 of the RYR1 gene, resulting in deletion of the conserved glutamic acid at position 2347. The deletion of glu2347 was accompanied by an unusually large electrically evoked contraction tension in the in vitro diagnostic pharmacologic contracture test in MH-positive persons, suggesting that this deletion produces an alteration in skeletal muscle calcium regulation, even in the absence of pharmacologic agents.
In affected members of a 4-generation family (CCD10) with autosomal dominant congenital myopathy-1A (CMYO1A; 117000), Monnier et al. (2001) identified a heterozygous 9-bp deletion (amino acids 12640-12648, 12640delCGCCAGTTC) in exon 91 of the RYR1 gene, eliminating the codons for arg4214, gln4215, and phe4216 from the transcript. The authors noted that these 3 amino acids are conserved among all 3 human RYR genes.
Among 7 of 25 unrelated individuals with congenital myopathy-1A (CMYO1A; 117000) with central cores on muscle biopsy, Tilgen et al. (2001) identified a heterozygous c.14582G-A transition in the RYR1 gene, resulting in an arg4861-to-his (R4861H) substitution at a highly conserved residue in the C-terminal region of the protein.
In affected members of 2 unrelated families (CCD07 and CCD15) and an unrelated patient (CCD09) with CMYO1A, Monnier et al. (2001) identified a heterozygous R4861H mutation in exon 101 of the RYR1 gene. The mutation occurred de novo in patient CCD09.
Quinlivan et al. (2003) identified a de novo heterozygous R4861H mutation in exon 101 of the RYR1 gene in an 11-year-old boy (family D) with CMYO1A. Functional studies of the variant were not performed. As an infant, he had hypotonia with poor feeding. He later showed delayed motor development, inability to walk independently, congenital hip dislocation, lordosis, and upper limb involvement.
Sato et al. (2008) identified heterozygosity for the R4861H mutation in a 6-month-old Japanese boy (patient 2) with CMYO1A manifest as 'congenital neuromuscular disease with uniform type 1 fiber' (CNMDU1). He had poor sucking, muscle weakness, joint contractures, and 99.9% type 1 muscle fibers on skeletal muscle biopsy.
In affected members of a consanguineous Algerian family (family 1) with autosomal recessive congenital myopathy-1B (CMYO1B; 255320) characterized by the presence of multiple, short-length core lesions (minicores) in both muscle fiber types, Ferreiro et al. (2002) identified homozygosity for a c.10579C-T transition in exon 71 of the RYR1 gene that resulted in a pro3527-to-ser (P3527S) substitution. Three children in the family presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity, hand involvement, and multiple minicores on skeletal muscle biopsy. New muscle biopsies from the 3 patients in adulthood demonstrated central core disease with rods; no cores were found in the healthy parents.
In a 19-year-old girl, born of consanguineous parents (family 1), with autosomal recessive congenital myopathy-1B (CMYO1B; 255320) with both multiminicores and cores on muscle biopsy and confirmed linkage to the RYR1 locus, Jungbluth et al. (2002) identified a homozygous c.14545G-A transition in exon 101 of the RYR1 gene, resulting in a val4849-to-ile (V4849I) substitution.
In a 9-year-old girl, born of consanguineous parents, with autosomal recessive CMYO1B and central core disease on muscle biopsy, Kossugue et al. (2007) identified a homozygous V4849I substitution in the RYR1 gene.
Monnier et al. (2008) reported a 9-year-old Dutch boy with a severe autosomal recessive myopathy with ptosis and facial diplegia associated with compound heterozygous mutations in the RYR1 gene: V4849I and a 4-bp insertion (180901.0032). The patient had severe neonatal hypotonia, delayed motor development, amyotrophy, kyphoscoliosis, required ventilatory assistance at age 4 years, and was never able to walk. A sister had died at age 5 years of myopathic respiratory insufficiency. Monnier et al. (2008) postulated that since the patient had a hypomorphic frameshift RYR1 allele, the resultant phenotype was more severe compared to those patients with homozygous V4849I mutations.
In affected members of a family with susceptibility to malignant hyperthermia (MHS1; 145600), Guis et al. (2004) identified heterozygosity for 2 mutations in the RYR1 gene on the same allele: an c.8026C-T transition in exon 50, resulting in an arg2676-to-trp (R2676W) substitution, and an c.8160C-G transversion in exon 53, resulting in a thr2787-to-ser (T2787S) substitution. Affected members of the family had an unusual clinical phenotype including multiminicore myopathy without clinical muscle involvement. Guis et al. (2004) suggested that the R2676W mutation is the candidate mutation responsible for MHS and that the T2787S mutation is a 'secondary aggravating' mutation leading to histologic multiminicores.
In DNA from a patient with congenital myopathy-1A (CMYO1A; 117000), Zorzato et al. (2003) detected a heterozygous deletion of nucleotides 14588 to 14606 in exon 101 of the RYR1 gene. The deletion was also detected in the patient's mildly affected mother. The deletion was predicted to result in the deletion of 7 amino acids (4863-4869, FYNKSED) and insertion of a novel tyrosine residue in the pore-forming region of the sarcoplasmic reticulum calcium release channel. Heterologous expression of recombinant RYR1 peptides and analysis of their membrane topology demonstrated that the deleted amino acids are localized in the luminal loop connecting membrane-spanning segments M8 and M10.
In a 17-year-old Tunisian boy, born of first-cousin parents, with congenital myopathy-1B (CMYO1B; 255320) manifest as multiminicore disease with ophthalmoplegia, Monnier et al. (2003) identified a homozygous 119-bp insertion at position 14646 of the RYR1 gene and an A-to-G transition at position +1 from the insertion fragment, resulting in a frameshift of the last 94 amino acids downstream of the insertion site and a premature stop codon. The mutation, designated 14646+2.99 kb A-to-G, resulted in a 90% decrease of the normal RYR1 transcript in skeletal muscle. The mutation was not expressed in lymphoblastoid cells, suggesting a tissue-specific splicing mechanism.
In 2 sibs with congenital myopathy-1B (CMYO1B; 255320) manifest as minicore myopathy with external ophthalmoplegia, Jungbluth et al. (2005) identified a c.325C-T transition in exon 4 of the RYR1 gene, resulting in an arg109-to-trp (R109W) substitution in a highly conserved region. Analysis of cDNA showed homozygosity for the mutation, but genomic DNA showed heterozygosity. Jungbluth et al. (2005) postulated that the second allele was either not expressed or deleted and may indicate a promoter mutation or a large deletion. Haplotype analysis and the unaffected parental carrier status were consistent with biallelic mutations and autosomal recessive inheritance.
Klein et al. (2012) reanalyzed one of these patients as patient 41 and identified an additional missense and nonsense mutation.
In 3 sibs with congenital myopathy-1B (CMYO1B; 255320) manifest as minicore myopathy with external ophthalmoplegia originally reported by Swash and Schwartz (1981), Jungbluth et al. (2005) identified a c.7268T-A transversion in exon 45 the RYR1 gene, resulting in a met2423-to-lys substitution in a highly conserved region. Analysis of cDNA showed homozygosity for the mutation, but genomic DNA showed heterozygosity. Jungbluth et al. (2005) postulated that the second allele was either not expressed or deleted and may indicate a promoter mutation or a large deletion. Haplotype analysis and the unaffected parental carrier status were consistent with biallelic mutations and autosomal recessive inheritance.
Klein et al. (2012) reanalyzed one of these patients as patient 44 and identified a W661X mutation in trans with the M2423 allele.
In 2 sibs (family 5) with congenital myopathy-1B (CMYO1B; 255320) manifest as minicore myopathy with external ophthalmoplegia, Jungbluth et al. (2005) identified compound heterozygosity for 2 mutations in the RYR1 gene: an A-to-T transversion in intron 99 (c.14365-2A-T), resulting in a splice site mutation, and a c.10349C-T transition in exon 68, resulting in a ser3450-to-phe (S3450F) substitution (180901.0029).
For discussion of the ser3450-to-phe (S3450F) mutation in the RYR1 gene that was found in 2 sibs with congenital myopathy-1B (CMYO1B; 255320) by Jungbluth et al. (2005), see 180901.0028.
In affected members of a large family with autosomal dominant congenital myopathy-1A (CMYO1A; 117000), Scacheri et al. (2000) identified a heterozygous c.13996A-G transition in exon 95 of the RYR1 gene, resulting in a thr4637-to-ala (T4637A) substitution within the transmembrane domain. Skeletal muscle biopsies from 2 affected individuals showed the presence of central cores in over 85% of myofibers and nemaline rods in 5 to 25% of myofibers.
In affected members of a French family with malignant hyperthermia (MHS1; 145600), Quane et al. (1994) identified a heterozygous c.1565A-C transversion in the RYR1 gene, resulting in a tyr522-to-ser (Y522S) substitution. Skeletal muscle biopsies from 2 patients in this family showed central cores in the absence of clinical features of a myopathy.
In a 9-year-old Dutch boy with a severe form of autosomal recessive congenital myopathy-1B (CMYO1B; 255320), Monnier et al. (2008) detected compound heterozygous mutations in the RYR1 gene: V4849I (180901.0022) and a 4-bp insertion (c.1742insATCA). The patient had severe neonatal hypotonia, delayed motor development, amyotrophy, kyphoscoliosis, required ventilatory assistance at age 4 years, and was never able to walk. A sister had died at age 5 years of myopathic respiratory insufficiency. The 4-bp insertion was predicted to result in a premature stop codon and an unstable truncated protein.
In an 11-year-old Japanese patient with congenital myopathy-1A (CMYO1A; 117000), Sato et al. (2008) identified a heterozygous 2-bp deletion/2-bp insertion (c.14761delTTinsAC) in exon 102 of the RYR1 gene, resulting in a phe4921-to-thr (F4921T) substitution. The patient had delayed motor milestones, proximal muscle weakness, and uniform type 1 fibers on muscle biopsy. The patient's affected father, who carried the same mutation (Wu et al., 2006), showed typical central cores on muscle biopsy. The family had previously been reported by Tojo et al. (2000).
In an 8-year-old Japanese patient (P1) with congenital myopathy-1A (CMYO1A; 117000), Sato et al. (2008) identified a heterozygous 20-bp deletion beginning in exon 91 of the RYR1 gene and predicted to result in premature termination and removal of 464 residues from the C terminus of the protein (Ala4338fs).
In 1 South African patient (patient 1) with a severe form of autosomal recessive congenital myopathy-1B (CMYO1B; 255320), Wilmshurst et al. (2010) identified compound heterozygosity for 2 alleles containing complex mutations in the RYR1 gene: 1 allele carried a 2-bp deletion (5726delAG) in exon 35 and a 9242T-C transition in exon 63, resulting in a met3081-to-thr (M3081T) substitution, and the other allele carried a splice site mutation and a V4842M substitution (180901.0036). The 2-bp del/M3081T allele was also found in patient 12, also South African, in whom a mutation on the second allele was not identified. Haplotype analysis indicated a founder effect in the South African population. The phenotype was characterized by onset at birth, neonatal hypotonia and weakness, delayed motor development, external ophthalmoplegia, and bulbar involvement. Histopathologic findings included central nuclei, multiple internalized nuclei, type 1 fiber predominance and hypotrophy, relative type 2 hypertrophy, and oxidative abnormalities in electron microscopic analysis, although frank cores were not typically seen.
In 11 South African patients with a severe form of autosomal recessive congenital myopathy-1B (CMYO1B; 255320), Wilmshurst et al. (2010) found a common complex allele containing 2 mutations in the RYR1 gene: a C-to-G transversion in intron 68 (10348-6C-G) and a 14524G-A transition in exon 101, resulting in a val4842-to-met (V4842M) substitution. The splice site mutation results in the production of an aberrant transcript that includes intron 68 and introduces a premature stop codon (His3449ins33fsTer54), but penetrance of this mutation is incomplete, resulting in the expression of both spliced and unspliced transcripts (Monnier et al., 2008). Wilmshurst et al. (2010) hypothesized that this allele determines the phenotype by 2 interrelated mechanisms: by reducing the amount of the RYR1 protein and by the V4842M substitution on residual protein. Haplotype analysis indicated a founder effect in the South African population, but Monnier et al. (2008) also found it in 2 sibs from Chile with severe neonatal hypotonia. All except 1 of the 11 patients were compound heterozygous for this allele and another pathogenic allele affecting the RYR1 gene (see, e.g., 180901.0035 and 180901.0037). The phenotype was characterized by onset at birth, neonatal hypotonia and weakness, delayed motor development, external ophthalmoplegia, and bulbar involvement. Histopathologic findings included central nuclei, multiple internalized nuclei, type 1 fiber predominance and hypotrophy, relative type 2 hypertrophy, and oxidative abnormalities in electron microscopic analysis, although frank cores were not typically seen.
In 3 South African patients with a severe form of autosomal recessive congenital myopathy-1B (CMYO1B; 255320), Wilmshurst et al. (2010) identified compound heterozygosity for 2 alleles containing complex mutations in the RYR1 gene: 1 allele carried a 2-bp deletion in exon 53 (8342delTA) and a 11941C-T transition in exon 87, resulting in a his3981-to-tyr (H3981Y) substitution, and the other allele carried a splice site mutation and a V4842M substitution (180901.0036). Haplotype analysis indicated a founder effect in the South African population. The phenotype was characterized by onset at birth, neonatal hypotonia and weakness, delayed motor development, external ophthalmoplegia, and bulbar involvement. Histopathologic findings included central nuclei, multiple internalized nuclei, type 1 fiber predominance and hypotrophy, relative type 2 hypertrophy, and oxidative abnormalities in electron microscopic analysis, although frank cores were not typically seen.
In a 27-year-old woman with King-Denborough syndrome (KDS; 619542), D'Arcy et al. (2008) identified a heterozygous c.97A-G transition in exon 2 of the RYR1 gene, resulting in a lys33-to-glu (K33E) substitution at a highly conserved residue. The mutation was not present in other family members or in 200 normal controls. She was born at term after a pregnancy complicated by decreased fetal movements and breech presentation. At birth, she was noted to have hypotonia, ptosis, high-arched palate, prominent philtrum, and scaphocephaly. The father and paternal grandfather had congenital ptosis, but no other signs of neuromuscular disease. She underwent surgery for ptosis at ages 2 and 9 years without complications. Facial and proximal limb weakness became more apparent with age, and she developed kyphoscoliosis, myopathic facies with flat midface, prominent columella, and webbed neck. An EMG was myopathic and serum creatine kinase was increased. At age 15 years, she developed hyperthermia during surgery for scoliosis repair, and subsequent muscle testing confirmed susceptibility to malignant hyperthermia.
In 6 fetuses, conceived by consanguineous Dutch parents, with congenital myopathy-1B (CMYO1B; 255320) presenting as lethal fetal akinesia, McKie et al. (2014) identified a homozygous c.6721C-T transition (c.6721C-T, NM_000540.2) in the RYR1 gene, resulting in an arg2241-to-ter (R2241X) substitution. The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. A heterozygous c.6721C-T transition (rs200563280) had been found in 1 of 6,503 genotypes in the Exome Variant Server database.
In 2 fetuses, conceived by consanguineous Pakistani parents, with congenital myopathy-1B (CMYO1B; 255320) presenting as lethal fetal akinesia, McKie et al. (2014) identified a homozygous 27-bp deletion (c.2097_2123del, NM_000540.2) in the RYR1 gene that removes 9 conserved amino acids from the SPRY2 domain and replaces glu699 with asp (glu699_gly707del). Each unaffected parent was heterozygous for the mutation. The family was 1 of 36 with a similar lethal phenotype who underwent direct sequencing of the RYR1 gene. Functional studies of the variant were not performed.
In 2 fetuses, conceived of consanguineous Palestinian parents, with congenital myopathy-1B (CMYO1B; 255320) presenting as lethal fetal akinesia, McKie et al. (2014) identified a homozygous 3-bp deletion (c.7043_7045delGAG, NM_000540.2) in the RYR1 gene, resulting in the deletion of the conserved residue glu2347 (E2347del). Each unaffected parent was heterozygous for the mutation. The family was 1 of 36 with a similar phenotype who underwent direct sequencing of the RYR1 gene. Functional studies of the variant were not performed. A different 3-bp deletion results in the deletion of the same residue (180901.0017).
In a 14-year-old proband (patient 2) with King-Denborough syndrome (KDS; 619542), Dowling et al. (2011) identified heterozygosity for a c.7354C-T transition in exon 46 of the RYR1 gene, resulting in an arg2452-to-trp (R2452W) substitution at a highly conserved residue. The mutation, which was found by RYR1 gene sequencing, was also identified in the boy's symptomatic mother and sib.
In a 2-year-old boy with King-Denborough syndrome (KDS; 619542), Joseph et al. (2017) identified heterozygosity for an c.7522C-T transition in the RYR1 gene, resulting in an arg2508-to-cys (R2508C) substitution. The mutation was identified by RYR1 gene sequencing. Functional studies were not performed.
In affected members of 2 unrelated families (CCD04 and CCD08) with autosomal dominant congenital myopathy-1A (CMYO1A; 117000), Monnier et al. (2001) identified a heterozygous c.14677C-T transition in exon 102 of the RYR1 gene, resulting in an arg4893-to-trp (R4893W) substitution in the C-terminal domain.
In 3 members of a 2-generation Asian family (family B) with CMYO1A, Quinlivan et al. (2003) identified a heterozygous R4893W mutation in the RYR1 gene. The mutation occurred in region 3 in the C terminus.
In 4 affected individuals from a 2-generation family (family C) with autosomal dominant congenital myopathy-1A (CMYO1A; 117000), Quinlivan et al. (2003) identified a heterozygous mutation in the RYR1 gene, resulting in a tyr4864-to-cys (R4864C) substitution in exon 102. The mutation occurred in region 3 in the C terminus. Of note, a 44-year-old male family member who carried the mutation was unaffected, suggesting incomplete penetrance, although he had a son with a congenital foot deformity who was not studied. Functional studies of the variant were not performed.
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