ArticleAmerican journal of physiology. Cell physiology2010
Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit.
Article in American journal of physiology. Cell physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 54 citations in OpenAlex.
- Trial
- Pathogenic CaCommunications biology · 2026Article
- Article
- A novel CACNA1S gene variant in a child with hypokalemic periodic paralysis: a case report and literature review.BMC pediatrics · 2023Review
- CaHandbook of experimental pharmacology · 2023Article
- A reconstituted depolarization-induced Ca2+ release platform for validation of skeletal muscle disease mutations and drug discovery.The Journal of general physiology · 2022Article
- Article
- CACNA1S haploinsufficiency confers resistance to New World arenavirus infection.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Skeletal muscle CaPflugers Archiv : European journal of physiology · 2020Review
- PharmGKB summary: very important pharmacogene information for CACNA1S.Pharmacogenetics and genomics · 2020Article
- Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-βAmerican journal of physiology. Cell physiology · 2018Article
- Mechanisms Responsible for ω-Pore Currents in CaBiophysical journal · 2017Article
- Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Excitation-Contraction Coupling Alterations in Myopathies.Journal of neuromuscular diseases · 2016Review
- Skeletal Muscle Microalterations in Patients Carrying Malignant Hyperthermia-Related Mutations of the e-c Coupling Machinery.European journal of translational myology · 2016Article
- Comparison of pathogenicity prediction tools on missense variants in RYR1 and CACNA1S associated with malignant hyperthermia.British journal of anaesthesia · 2016Article
- The couplonopathies: A comparative approach to a class of diseases of skeletal and cardiac muscle.The Journal of general physiology · 2015Review
- How is SR calcium release in muscle modulated by PIP(4,5)2?The Journal of general physiology · 2015Article
- Channelopathies of skeletal muscle excitability.Comprehensive Physiology · 2015Review
- Actionable exomic incidental findings in 6503 participants: challenges of variant classification.Genome research · 2015Article
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Authors and funding
9 authors at 4 institutions in 3 countries.
Funding
Abstract
To identify the genetic locus responsible for malignant hyperthermia susceptibility (MHS) in an Italian family, we performed linkage analysis to recognized MHS loci. All MHS individuals showed cosegregation of informative markers close to the voltage-dependent Ca(2+) channel (Ca(V)) α(1S)-subunit gene (CACNA1S) with logarithm of odds (LOD)-score values that matched or approached the maximal possible value for this family. This is particularly interesting, because so far MHS was mapped to >178 different positions on the ryanodine receptor (RYR1) gene but only to two on CACNA1S. Sequence analysis of CACNA1S revealed a c.4060A>T transversion resulting in amino acid exchange T1354S in the IVS5-S6 extracellular pore-loop region of Ca(V)α(1S) in all MHS subjects of the family but not in 268 control subjects. To investigate the impact of mutation T1354S on the assembly and function of the excitation-contraction coupling apparatus, we expressed GFP-tagged α(1S)T1354S in dysgenic (α(1S)-null) myotubes. Whole cell patch-clamp analysis revealed that α(1S)T1354S produced significantly faster activation of L-type Ca(2+) currents upon 200-ms depolarizing test pulses compared with wild-type GFP-α(1S) (α(1S)WT). In addition, α(1S)T1354S-expressing myotubes showed a tendency to increased sensitivity for caffeine-induced Ca(2+) release and to larger action-potential-induced intracellular Ca(2+) transients under low (≤ 2 mM) caffeine concentrations compared with α(1S)WT. Thus our data suggest that an additional influx of Ca(2+) due to faster activation of the α(1S)T1354S L-type Ca(2+) current, in concert with higher caffeine sensitivity of Ca(2+) release, leads to elevated muscle contraction under pharmacological trigger, which might be sufficient to explain the MHS phenotype.
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