Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia
Abstract
A review of the pharmacogenetics (PGt) and pathophysiology of calcium voltage-gated channel subunit alpha1 S (CACNA1S) mutations in malignant hyperthermia susceptibility type 5 (MHS5; MIM #60188) is presented. Malignant hyperthermia (MH) is a life-threatening hypermetabolic state of skeletal muscle usually induced by volatile, halogenated anesthetics and/or the depolarizing neuromuscular blocker succinylcholine. In addition to ryanodine receptor 1 (RYR1) mutations, several CACNA1S mutations are known to be risk factors for increased susceptibility to MH (MHS). However, the presence of these pathogenic CACNA1S gene variations cannot be used to positively predict MH since the condition is genetically heterogeneous with variable expression and incomplete penetrance. At present, one or at most six CACNA1S mutations display significant linkage or association either to clinically diagnosed MH or to MHS as determined by contracture testing. Additional pathogenic variants in CACNA1S, either alone or in combination with genes affecting Ca2+ homeostasis, are likely to be discovered in association to MH as whole exome sequencing becomes more commonplace.
Malignant Hyperthermia
malignant hyperthermia (MH) is an autosomal dominant, multifactorial pharmacogenetic condition of skeletal muscle that is induced by exposure to volatile anesthetics and/or to succinylcholine. The frequency of occurrence of MH is ~1 in 5,000 to 1 in 50,000 instances, i.e., where a susceptible individual receives an inhaled anesthetic agent and/or succinylcholine (25). This frequency may be an underestimate as a number of individuals carrying genetic risk alleles are not exposed to the potential trigger agents. Roughly 50–70% of total MH cases have been found to be linked to mutations within the ryanodine receptor 1 (RYR1) gene (53), with the calcium voltage-gated channel subunit alpha1 S (CACNA1S) gene accounting for approximately the next 1% (58). Most of the remaining cases have not been genetically characterized or may not have a genetic basis. Patients with MH usually first show signs of tachycardia and hypercapnia (61) usually followed by hyperthermia, muscle rigidity, acidosis, hypoxia, and increased creatine kinase concentration from rhabdomyolysis, which can lead to renal failure (6, 52). If the hypermetabolic condition is not promptly treated with dantrolene, an inhibitor of Ca2+ release from the sarcoplasmic reticulum (19, 21, 45), malignant hyperthermia is almost always fatal.
Testing for MH and Malignant Hyperthermia Susceptibility
Malignant hyperthermia susceptibility (MHS) genotyping is a first-line strategy for detecting pathogenic gene variants in MH-susceptible individuals. Invasive in vitro contracture testing (IVCT) of biopsied muscle is performed in Europe and caffeine halothane contracture testing is performed in North America as an adjunct to genetic testing. Next-generation whole exome sequencing (NGS-WES) will become more common as the cost for testing diminishes, analysis becomes less time-consuming, and the number of Clinical Laboratory Improvement Amendments-certified laboratories offering NGS-WES expands (41).
Pathophysiology of MH
The pathophysiology of MH involves a dysregulation of Ca2+ transport primarily caused by abnormal functioning of the skeletal muscle excitation-contraction (EC) coupling complex. The EC complex is localized to the T-tubule/sarcoplasmic reticulum (SR) junction of skeletal muscle. It responds to depolarization of the sarcolemma by promoting the release of Ca2+ from SR stores to activate muscle contraction. Muscle contraction is activated when Ca2+ binds to troponin (TnC), a regulatory protein of actin-myosin cross-bridge formation.
The EC complex consists of two main components. The first is a T-tubule localized, pentameric L-type Ca2+ channel (DHPR) (12, 54, 56) containing the Ca2+ channel-forming, voltage-sensing α1 subunit (Cav1.1) encoded by the gene CACNA1S. The second component of the EC complex is an SR membrane localized Ca2+-dependent, Ca2+ channel ryanodine receptor (RyR) encoded by the RYR1 gene (27) (Fig. 1). The physical interaction of the voltage-sensing α1 subunit of DHPR with the RyR Ca2+ channel provides the foundation for EC coupling (Fig. 2). Voltage-gated Ca2+ channel auxiliary subunit β (β1a) encoded by the gene CACNB1 is sometimes considered as a third main component of the EC complex. β1a binds to and mechanically alters the conformation of the II-III intracellular loops (Fig. 2) of the DHPR α1s subunit to support EC coupling (32).
Fig. 1.Channelopathies of Ca2+ channels, DHPR and RyR1, confer susceptibility to malignant hyperthermia. The CACNA1S alpha1 subunit (rainbow cube) of DHPR is the voltage sensor that interacts with RyR1 (purple) to allow excitation-contraction (EC) coupling.
Fig. 2.Subunit architecture and II-III loop coupling of the calcium voltage-gated channel subunit alpha1 S (CACNA1S) subunit (rainbow blocks) of DHPR to ryanodine receptor 1 (RyR1)(purple). Voltage induced-conformational changes in the alpha1 subunit are transmitted through the II–III loop-beta1a complex, and through direct interactions with RyR1, promote excitation-contraction (EC) coupling.
Genetic variation in RYR1 or CACNA1S may cause EC complex channelopathies. In the presence of inhaled anesthetic agents and/or the depolarizing neuromuscular blocking agent succinylcholine these channelopathies can lead to a dysregulated release of Ca2+ from the SR, uncontrolled contraction of skeletal muscle, and a resultant hypermetabolic state that is MH.
CACNA1S
CACNA1S, identified by other commonly used names (DHPRα1, Cav1.1, CACN1, CACNL1A3, MHS5) is required for normal skeletal muscle function. CACNA1S encodes the ~176 kDa α1 subunit of the ~450 kDa DHPR channel (9, 10, 29, 30). The α1 subunit has a total of four six-segment (S1–S6) transmembrane-spanning domains (I, II, III, IV) and three intracellular loop domains (loop I and II, loop II and III, loop III and IV; Fig. 3). The S4 segment of each repeated domain is thought to be the voltage sensor. CACNA1S spans ~90 kB on the long arm of chromosome 1 (1q32.1) and contains 44 exons (13). Exons of Cav channels are alternatively spliced to give the various Cav isoforms. Cav1.1 is the isoform predominantly expressed in skeletal muscle.
Fig. 3.The CACNA1S encoded alpha1 subunit of DHPR. The voltage sensing function (+) of the alpha1 subunit is due charged residues in the S4 transmembrane segments (I-4 through IV-4).
It is often reported that ~1% of MH cases are due to mutations within CACNA1S, though it is difficult to know if the CACNA1S mutations appear alone or in combination with untested mutations in other Ca2+ regulatory genes. Six clinically significant variants of CACNA1S with linkage or association to MH have been identified (Table 1), including the p.R1086H mutation that disrupts EC coupling (62) and the p.R174W mutation, which ablates the L-type current without affecting EC coupling (18). Whole exome sequencing has identified over 50 additional variants of CACNA1S, including 48 missense variations that are possible risk factors for MH (20, 39). Though variants in CACNA1S are prevalent in the general population, the MH risk attributed to almost all of these variants has not been established. Additionally, the penetrance of MH in populations carrying pathogenic CACNA1S mutations is unknown, primarily because of the low frequency with which these populations are exposed to volatile anesthetics and/or succinylcholine.
| CACNA1S Missense Variant | CACNA1S cDNA Variant | Molecular Localization of Variant | Single Nucleotide Polymorphism (allele frequency)* | Pathogenicity |
|---|---|---|---|---|
| p.Arg174Trp | CGG>TGG c.520C>T | IS4 voltage sensing segment | rs772226819 (NA) | T allele on coding strand is autosomal dominant and pathogenic as compared with allele C (8, 18) |
| p.Arg1086Cys | CGT>TGT CGC>TGC c.3256C>T | cytoplasmic region linking domains III and IV | rs80338782 (GO-ESP, 0.00015; GMAF, 0.0002) | T allele on coding strand may be pathogenic as compared with allele C; inferred from literature |
| p.Arg1086Ser | CGT>AGT CGC>AGC c.3256C>A | cytoplasmic region linking domains III and IV | rs80338782 (GO-ESP, 0.00003; GMAF, 0.0002) | A allele on coding strand is autosomal dominant and pathogenic as compared with allele C (60) |
| p.Arg1086His | CGC>CAC CGU>CAU c.3257G>A | cytoplasmic region linking domains III and IV | rs1800559 (NA) | A allele on coding strand is autosomal dominant and pathogenic as compared with allele G (37–39, 58, 62) |
| p.Arg1086Leu | CGt > CTT CGC>CTC CGA>CTA CGG>CTG c.3257G>T | cytoplasmic region linking domains III and IV | rs1800559 (NA) | T allele on coding strand is autosomal dominant and pathogenic as compared with allele G (62) |
| p.Thr1354Ser | ACA>AGT c.4060A>T | extracellular domain IV S5-S6 pore-loop | rs145910245 (GMAF: 0.00080, ExAC: 0.00236) | T allele on coding strand may be pathogenic as compared with allele A (47); T allele benign variant in linkage disequilibrium with an undetected pathogenic variant (20) |
CACNA1S Pathogenic Variants of Clinical Significance
The Pharmacogenomics Knowledgebase [PharmGKB (63)] designates level 3 evidence of pathogenicity for rs1800559 (CACNA1S, p.Arg1086His, c.3257) in relationship to administration of numerous inhalational anesthetics and a depolarizing neuromuscular blocking agent (Table 2). The level 3 designation is primarily based on two independent studies in which MHS patients were screened for CACNA1S mutations (63). Within one MH susceptible family (n = 17), a total of 12 individuals were found with the p.Arg1086His mutation. In this same study, the p.Arg1086His mutation was lacking in 106 unrelated, control samples (39). In another screen, the p.Arg1086His mutation was found in two of 112 IVCT-positive MHS samples and absent in 154 control samples (58).
| Volatile halogenated anesthetics |
| Desflurane |
| Enflurane |
| Halothane |
| Isoflurane |
| Methoxyflurane |
| Sevoflurane |
| Depolarizing neuromuscular blocker |
| Succinylcholine |
The clinical implication of the p.Arg1086His mutation is that patients with the AA or AG genotype on the coding strand (TT or TC on the noncoding strand) at c.3257 may be at risk for MH following administration of inhaled anesthetics and/or succinylcholine as compared with the normal GG genotype (CC on the noncoding strand).
Pharm GKB designates level 3 evidence of pathogenicity for rs772226819 (CACNA1S, p.Arg174Trp, c. 520C>T in relationship to administration of halothane or succinylcholine (Table 1). The T allele on the coding strand is autosomal dominant and pathogenic as compared with the C allele. Patients with the heterozygous CT or homozygous TT genotype on the coding strand (GA or AA on the noncoding strand) at c.520 may be at risk for MH following administration of halothane and/or succinylcholine as compared with the normal homozygous CC genotype (GG on the noncoding strand).
Though not annotated by PharmGKB, p.Arg1086Cys and p.Arg1086Ser mutations (c.3256; rs80338782) are likely risk factors for MH. One case of fulminant MH was reported in a patient who was found to be homozygous for the p.Arg1086Ser mutation (60). Using cDNA sequencing, another group discovered a novel mutation of CACNA1S at p.Arg174Trp (c.520) in 1 of 50 unrelated, RYR1-mutation negative MH patients (8).
A screen of 11 MHS individuals from the same MH proband family were found to possess a p.Thr1354Ser (c.4060; rs145910245) mutation that segregated with MHS as determined by positive IVCT. This same mutation was not found in 268 normal controls (47).
Combined, the results of these studies have provided enough evidence to designate the inhaled anesthetic agents/succinylcholine-CACNA1S drug(s)-gene interaction as “actionable PGx” (63). Based on this information, the use of potent halogenated anesthetics and/or succinylcholine is contraindicated in MHS patients carrying any of the six pathogenic CACNA1S mutations (Table 1).
Genetically Related Disorders Caused by CACNA1S Mutations
Variants in CACNA1S are associated with diseases other than MH. These diseases include hypokalemic periodic paralysis, type 1 (HOKPP1) and thyrotoxic periodic paralysis type 1 (TTPP1). HOKPP1 signs include occasional muscle weakness or paralysis, along with abnormally low serum potassium levels. In one study that enrolled 71 patients, HOKPP1 was most often found to be caused by p.R1239H or p.R528H mutations in CACNA1S (36). Both of these arginine mutations lie within the S4 voltage-sensing, transmembrane region of the channel (33, 57). The signs of TTPP1 are similar to HOKPP1, however the genetic factors differ. TTPP1 is observed to be linked to single nucleotide polymorphisms (SNPs) within the 5′ flanking region or within introns of CACNA1S. These SNPs are postulated to affect the ability of thyroid hormone to stimulate expression of the CACNA1S gene via the thyroid hormone response element (26).
Beyond RYR1 and CACNA1S: the Complex Genetics of MH
Genetic identification of those at risk for MH is challenging. Many individuals identified as having pathogenic mutations for MH, especially in the RYR1 gene, have not experienced MH episodes following anesthetic exposure, while others without any identified MHS gene mutations have been diagnosed with MH. Furthermore, very few patients exposed to anesthesia have MH episodes. This limits the number of samples available for genetic testing. Despite the challenges, linkage studies of MHS families and/or contracture testing of case/control biopsied muscle samples have confirmed many clinically important mutations in the RYR1 gene and at least six different susceptibility mutations in the CACNA1S gene.
The underlying genetic etiology of MH is complex primarily because so many interacting genes, besides CACNA1S and RYR1, impact Ca2+ homeostasis in skeletal muscle. Genetic variation in store-operated Ca2+ channels, for example, can affect the concentration of intracellular Ca2+ separately from that regulated by the EC complex (14). When Ca2+ is depleted from the SR during an MH episode, store-operated Ca2+ channels are activated to replenish the SR store. However, in MH, the SR store is depleted as quickly as it is replenished, and a rapidly progressing, positive feedback mechanism becomes difficult to abort.
Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) encodes an SR transmembrane Ca2+-ATPase that actively transports Ca2+ from the cytosol into the SR against the electrochemical gradient. Mutations in SERCA1 have been shown to cause an autosomal recessive form of Brody disease (31, 43, 44). Individuals with this myopathy experience increasing muscle spasticity during exercise that is marked by excessive cytosolic [Ca2+]. It would seem likely that an individual possessing a rare variation in CACNA1S, nonpathogenic on its own, combined with a second rare variation in SERCA1 or another gene, could be at an increased risk for MH.
Individuals with any myopathy, and possibly even those with strabismus (28), are at an increased risk of MH episodes. In one small population of native American Indians with a known myopathy, a mutation in SH3 and cysteine-rich domain 3 (STAC3) was found to be responsible for MH. Interestingly, the STAC3 mutation diminished excitation-contraction coupling (23). In other studies, it was shown that STAC3 modulates Ca2+ release from the SR (11, 42, 49, 50).
DHPR, Panx1, P2Y2R, and Cav3 colocalize in adult myofibers and are likely to interact (4). FKBP12, calmodulin, triadin, junctin, and calsequestrin (34, 40, 46, 51, 59) also modify EC coupling (7, 17). Superoxide dismutase (SOD1) mutant mice have reductions in SR Ca2+ release and L-type Ca2+ currents (5). MH may also be linked to the potassium voltage-gated channel subfamily A member 1 [KCNA1 (Kv1.1)] gene (35).
Clearly, MH genetic heterogeneity contributes to the lack of penetrance and discordance in MH families with CACNA1S mutations. Algorithms that are able to more positively predict MHS will ultimately need to coordinately consider the genetic variations of multiple interacting gene products.
CACNA2D1 Gene and the DHPR Subunits α2/δ1
Susceptibility to MH type 3 (MHS3) has been linked to chromosome position 7q21-q22, which contains the CACNA2D1 gene and an adjacent dinucleotide repeat marker D7S849. This single gene codes for the α2 and δ1 subunits of the pentameric DHPR Ca2+ channel. In several families, MHS3 has been linked to D7S849 (24). However, pathogenic mutations in the coding region of CACNA2D1 have not correspondingly been found to be linked to MHS3 (55).
Pharmacology of Drugs as Triggers of MH
Many drugs target ion channels but only two classes of drugs are known to target ion channels and are also commonly associated with MH (Table 2). Volatile halogenated inhaled anesthetics remove the Mg2+ inhibition of the RyR Ca2+ channel in MHS patients (15, 16). Succinylcholine, a depolarizing neuromuscular blocker, targets acetylcholine receptor (AChR) Na+ channels. Succinylcholine has been shown to worsen the severity of the MH response when coadministered with potent volatile anesthetics (1, 2, 48).
Few reports have conclusively shown that succinylcholine alone is able to induce fulminant MH in humans (22), even though the correlation has been demonstrated in animal models. In addition to being acetylcholinesterase resistant, succinylcholine causes Phase I neuromuscular block by acting as an agonist at nicotinic (NM) AChRs. When bound by succinylcholine, AChRs open, causing an influx of Na+ and efflux of K+ along with depolarization of the sarcolemma. Voltage-gated Na+ channels open in response to AChR activation and subsequently become inactivated. In the presence of succinylcholine, Na+ channels remain in the inactivated state, causing flaccid paralysis. Interestingly, halogenated inhalation anesthetics can promote phase II block upon prolonged succinylcholine administration. This phase II block causes muscle cell membrane potentials to gradually return to a resting state (3).
Volatile anesthetics alone are capable of triggering MH in susceptible individuals. In addition to their action of removing Mg2+ inhibition of RyR, they have been shown to activate Ca2+-dependent ATPases in the SR. Not surprisingly, volatile halogenated anesthetics also exert effects on a wide range of other intracellular targets beyond the scope of this review.
Conclusion
CACNA1S is one of several genes with linkage to MH; however, the genetic complexity of MH serves as a prime example of the importance of bioinformatics and 'omics in clinical medicine. Multiple gene products coordinately operate to maintain Ca2+ homeostasis in skeletal muscle. When this homeostasis is disrupted by halogenated anesthetics and/or succinylcholine, single gene variations in CACNA1S may sometimes reveal themselves to be pathogenic. At other times, depending on the genotypic and metabolic status of the patient, they may remain phenotypically silent.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
T. A. Beam sourced citations and prepared and revised manuscript E. F. Loudermilk sourced citations and prepared figures D. F. Kisor sourced citations and prepared and revised manuscript.
REFERENCES
- 1. . Creatine kinase alterations after acute malignant hyperthermia episodes and common surgical procedures. Anesth Analg 81: 1039–1042, 1995.
PubMed | ISI | Google Scholar - 2. . Hyperkalaemia associated with haemorrhagic shock in rabbits: modification by succinylcholine, vecuronium and blood transfusion. Acta Anaesthesiol Scand 39: 1125–1127, 1995. doi:10.1111/j.1399-6576.1995.tb04242.x.
Crossref | PubMed | ISI | Google Scholar - 3. . Pharmacology of neuromuscular blocking drugs. Contin Educ Anaesth Crit Care Pain 4: 2–7, 2004. doi:10.1093/bjaceaccp/mkh002.
Crossref | Google Scholar - 4. . Characterization of a multiprotein complex involved in excitation-transcription coupling of skeletal muscle. Skelet Muscle 6: 15, 2016. doi:10.1186/s13395-016-0087-5.
Crossref | PubMed | ISI | Google Scholar - 5. . Progressive impairment of CaV1.1 function in the skeletal muscle of mice expressing a mutant type 1 Cu/Zn superoxide dismutase (G93A) linked to amyotrophic lateral sclerosis. Skelet Muscle 6: 24, 2016. doi:10.1186/s13395-016-0094-6.
Crossref | PubMed | ISI | Google Scholar - 6. . Rhabdomyolysis and acute kidney injury. N Engl J Med 361: 62–72, 2009. doi:10.1056/NEJMra0801327.
Crossref | PubMed | ISI | Google Scholar - 7. . The disorders of the calcium release unit of skeletal muscles: what have we learned from mouse models? J Muscle Res Cell Motil 36: 61–69, 2015. doi:10.1007/s10974-014-9396-7.
Crossref | PubMed | ISI | Google Scholar - 8. . The role of CACNA1S in predisposition to malignant hyperthermia. BMC Med Genet 10: 104, 2009. doi:10.1186/1471-2350-10-104.
Crossref | PubMed | ISI | Google Scholar - 9. . Molecular properties of voltage-sensitive sodium and calcium channels. Braz J Med Biol Res 21: 1129–1144, 1988.
PubMed | ISI | Google Scholar - 10. . Structure and function of voltage-sensitive ion channels. Science 242: 50–61, 1988. doi:10.1126/science.2459775.
Crossref | PubMed | ISI | Google Scholar - 11. . The SH3 and cysteine-rich domain 3 (Stac3) gene is important to growth, fiber composition, and calcium release from the sarcoplasmic reticulum in postnatal skeletal muscle. Skelet Muscle 6: 17, 2016. doi:10.1186/s13395-016-0088-4.
Crossref | PubMed | ISI | Google Scholar - 12. . Purification of the calcium antagonist receptor of the voltage-sensitive calcium channel from skeletal muscle transverse tubules. Biochemistry 23: 2113–2118, 1984. doi:10.1021/bi00305a001.
Crossref | PubMed | ISI | Google Scholar - 13. . The gene coding for the alpha 1 subunit of the skeletal dihydropyridine receptor (Cchl1a3 = mdg) maps to mouse chromosome 1 and human 1q32. Mamm Genome 4: 499–503, 1993. doi:10.1007/BF00364784.
Crossref | PubMed | ISI | Google Scholar - 14. . Store-operated Ca2+ entry in malignant hyperthermia-susceptible human skeletal muscle. J Biol Chem 285: 25645–25653, 2010. doi:10.1074/jbc.M110.104976.
Crossref | PubMed | ISI | Google Scholar - 15. . Mg2+ dependence of halothane-induced Ca2+ release from the sarcoplasmic reticulum in skeletal muscle from humans susceptible to malignant hyperthermia. Anesthesiology 101: 1339–1346, 2004. doi:10.1097/00000542-200412000-00014.
Crossref | PubMed | ISI | Google Scholar - 16. . Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia. Br J Anaesth 97: 320–328, 2006. doi:10.1093/bja/ael179.
Crossref | PubMed | ISI | Google Scholar - 17. . Core skeletal muscle ryanodine receptor calcium release complex. Clin Exp Pharmacol Physiol 44: 3–12, 2017. doi:10.1111/1440-1681.12676.
Crossref | PubMed | ISI | Google Scholar - 18. . Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor. Proc Natl Acad Sci U S A 109: 7923–7928, 2012. doi:10.1073/pnas.1119207109.
Crossref | PubMed | ISI | Google Scholar - 19. . Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors. J Biol Chem 272: 26965–26971, 1997. doi:10.1074/jbc.272.43.26965.
Crossref | PubMed | ISI | Google Scholar - 20. . Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology 119: 1043–1053, 2013. doi:10.1097/ALN.0b013e3182a8a8e7.
Crossref | PubMed | ISI | Google Scholar - 21. . Effect of dantrolene sodium on calcium movements in single muscle fibres. Nature 252: 728–730, 1974. doi:10.1038/252728a0.
Crossref | PubMed | ISI | Google Scholar - 22. . Malignant hyperthermia: pharmacology of triggering. Br J Anaesth 107: 48–56, 2011. doi:10.1093/bja/aer132.
Crossref | PubMed | ISI | Google Scholar - 23. . Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun 4: 1952, 2013. doi:10.1038/ncomms2952.
Crossref | PubMed | ISI | Google Scholar - 24. . Localization of the gene encoding the alpha 2/delta-subunits of the L-type voltage-dependent calcium channel to chromosome 7q and analysis of the segregation of flanking markers in malignant hyperthermia susceptible families. Hum Mol Genet 3: 969–975, 1994. doi:10.1093/hmg/3.6.969.
Crossref | PubMed | ISI | Google Scholar - 25. . Malignant hyperthermia. Korean J Anesthesiol 63: 391–401, 2012. doi:10.4097/kjae.2012.63.5.391.
Crossref | PubMed | Google Scholar - 26. . Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis. J Clin Endocrinol Metab 89: 1340–1345, 2004. doi:10.1210/jc.2003-030924.
Crossref | PubMed | ISI | Google Scholar - 27. . Ryanodine receptors: structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2: a003996, 2010. doi:10.1101/cshperspect.a003996.
Crossref | PubMed | ISI | Google Scholar - 28. . A case of malignant hyperthermia during anesthesia induction with sevoflurane -A case report-. Korean J Anesthesiol 59, Suppl: S6–S8, 2010. doi:10.4097/kjae.2010.59.S.S6.
Crossref | PubMed | Google Scholar - 29. . Structural characterization of the 1,4-dihydropyridine receptor of the voltage-dependent Ca2+ channel from rabbit skeletal muscle. Evidence for two distinct high molecular weight subunits. J Biol Chem 262: 7943–7946, 1987.
PubMed | ISI | Google Scholar - 30. . Fluorescence studies on the Ca2+ and Zn2+ binding properties of the alpha-subunit of bovine brain S-100a protein. FEBS Lett 214: 35–40, 1987. doi:10.1016/0014-5793(87)80008-X.
Crossref | PubMed | ISI | Google Scholar - 31. . Structure/function analysis of the Ca2+ binding and translocation domain of SERCA1 and the role in Brody disease of the ATP2A1 gene encoding SERCA1. Ann N Y Acad Sci 834: 175–185, 1997. doi:10.1111/j.1749-6632.1997.tb52249.x.
Crossref | PubMed | ISI | Google Scholar - 32. . Fluorescence resonance energy transfer-based structural analysis of the dihydropyridine receptor α1S subunit reveals conformational differences induced by binding of the β1a subunit. J Biol Chem 291: 13762–13770, 2016. doi:10.1074/jbc.M115.704049.
Crossref | PubMed | ISI | Google Scholar - 33. . Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology 72: 1544–1547, 2009. doi:10.1212/01.wnl.0000342387.65477.46.
Crossref | PubMed | ISI | Google Scholar - 34. . Silencing genes of sarcoplasmic reticulum proteins clarifies their roles in excitation-contraction coupling. J Physiol 587: 3089–3090, 2009. doi:10.1113/jphysiol.2009.171835.
Crossref | PubMed | ISI | Google Scholar - 35. . A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia. Neurogenetics 17: 245–249, 2016. doi:10.1007/s10048-016-0486-0.
Crossref | PubMed | ISI | Google Scholar - 36. . Correlating phenotype and genotype in the periodic paralyses. Neurology 63: 1647–1655, 2004. doi:10.1212/01.WNL.0000143383.91137.00.
Crossref | PubMed | ISI | Google Scholar - 37. . Correlations between genotype and pharmacological, histological, functional, and clinical phenotypes in malignant hyperthermia susceptibility. Hum Mutat 26: 413–425, 2005. doi:10.1002/humu.20231.
Crossref | PubMed | ISI | Google Scholar - 38. . Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility. Anesthesiology 97: 1067–1074, 2002. doi:10.1097/00000542-200211000-00007.
Crossref | PubMed | ISI | Google Scholar - 39. . Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet 60: 1316–1325, 1997. doi:10.1086/515454.
Crossref | PubMed | ISI | Google Scholar - 40. . Role of the JP45-calsequestrin complex on calcium entry in slow twitch skeletal muscles. J Biol Chem 291: 14555–14565, 2016. doi:10.1074/jbc.M115.709071.
Crossref | PubMed | ISI | Google Scholar - 41. . Exome sequencing: one small step for malignant hyperthermia, one giant step for our specialty–why exome sequencing matters to all of us, not just the experts. Anesthesiology 119: 1006–1008, 2013. doi:10.1097/ALN.0b013e3182a8a90c.
Crossref | PubMed | ISI | Google Scholar - 42. . Skeletal muscle-specific T-tubule protein STAC3 mediates voltage-induced Ca2+ release and contractility. Proc Natl Acad Sci U S A 110: 11881–11886, 2013. doi:10.1073/pnas.1310571110.
Crossref | PubMed | ISI | Google Scholar - 43. . The mutation of Pro789 to Leu reduces the activity of the fast-twitch skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1) and is associated with Brody disease. Hum Genet 106: 482–491, 2000. doi:10.1007/s004390000297.
Crossref | PubMed | ISI | Google Scholar - 44. . Mutations in the gene-encoding SERCA1, the fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ ATPase, are associated with Brody disease. Nat Genet 14: 191–194, 1996. doi:10.1038/ng1096-191.
Crossref | PubMed | ISI | Google Scholar - 45. . Essential role of calmodulin in RyR inhibition by dantrolene. Mol Pharmacol 88: 57–63, 2015. doi:10.1124/mol.115.097691.
Crossref | PubMed | ISI | Google Scholar - 46. . Reorganized stores and impaired calcium handling in skeletal muscle of mice lacking calsequestrin-1. J Physiol 583: 767–784, 2007. doi:10.1113/jphysiol.2007.138024.
Crossref | PubMed | ISI | Google Scholar - 47. . Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit. Am J Physiol Cell Physiol 299: C1345–C1354, 2010. doi:10.1152/ajpcell.00008.2010.
Link | ISI | Google Scholar - 48. . Suspected malignant hyperthermia reactions in New Zealand. Anaesth Intensive Care 30: 453–461, 2002.
PubMed | ISI | Google Scholar - 49. . Stac3 has a direct role in skeletal muscle-type excitation-contraction coupling that is disrupted by a myopathy-causing mutation. Proc Natl Acad Sci U S A 113: 10986–10991, 2016. doi:10.1073/pnas.1612441113.
Crossref | PubMed | ISI | Google Scholar - 50. . Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proc Natl Acad Sci U S A 112: 602–606, 2015. doi:10.1073/pnas.1423113112.
Crossref | PubMed | ISI | Google Scholar - 51. . Calsequestrin-1: a new candidate gene for malignant hyperthermia and exertional/environmental heat stroke. J Physiol 587: 3095–3100, 2009. doi:10.1113/jphysiol.2009.171967.
Crossref | PubMed | ISI | Google Scholar - 52. . Malignant hyperthermia–an update for perioperative nurses. ORNAC J 33: 16–26, 2015.
PubMed | Google Scholar - 53. . Mutations in RYR1 in malignant hyperthermia and central core disease. Hum Mutat 27: 977–989, 2006. doi:10.1002/humu.20356.
Crossref | PubMed | ISI | Google Scholar - 54. . Specific phosphorylation of a COOH-terminal site on the full-length form of the alpha 1 subunit of the skeletal muscle calcium channel by cAMP-dependent protein kinase. J Biol Chem 267: 16100–16105, 1992.
PubMed | ISI | Google Scholar - 55. . Genomic structure and functional expression of a human alpha(2)/delta calcium channel subunit gene (CACNA2). Genomics 61: 201–209, 1999. doi:10.1006/geno.1999.5941.
Crossref | PubMed | ISI | Google Scholar - 56. . Affinity purification of antibodies specific for 1,4-dihydropyridine Ca2+ channel blockers. Circ Res 61: I37–I45, 1987.
PubMed | ISI | Google Scholar - 57. . Gating pore current in an inherited ion channelopathy. Nature 446: 76–78, 2007. doi:10.1038/nature05598.
Crossref | PubMed | ISI | Google Scholar - 58. . Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia. Clin Genet 59: 178–184, 2001. doi:10.1034/j.1399-0004.2001.590306.x.
Crossref | PubMed | ISI | Google Scholar - 59. . Calsequestrin (CASQ1) rescues function and structure of calcium release units in skeletal muscles of CASQ1-null mice. Am J Physiol Cell Physiol 302: C575–C586, 2012. doi:10.1152/ajpcell.00119.2011.
Link | ISI | Google Scholar - 60. . A report of fulminant malignant hyperthermia in a patient with a novel mutation of the CACNA1S gene. Can J Anaesth 57: 689–693, 2010. doi:10.1007/s12630-010-9314-4.
Crossref | PubMed | ISI | Google Scholar - 61. . Anesthetic drugs and onset of malignant hyperthermia. Anesth Analg 118: 388–396, 2014. doi:10.1213/ANE.0000000000000062.
Crossref | PubMed | ISI | Google Scholar - 62. . Functional analysis of the R1086H malignant hyperthermia mutation in the DHPR reveals an unexpected influence of the III-IV loop on skeletal muscle EC coupling. Am J Physiol Cell Physiol 287: C1094–C1102, 2004. doi:10.1152/ajpcell.00173.2004.
Link | ISI | Google Scholar - 63. . Pharmacogenomics knowledge for personalized medicine. Clin Pharmacol Ther 92: 414–417, 2012. doi:10.1038/clpt.2012.96.
Crossref | PubMed | ISI | Google Scholar
