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Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Novel ryanodine receptor mutation that may cause malignant hyperthermia
Alexius Kaufmann1, Birgit Kraft, Andrea Michalek-Sauberer
1Department of Special Anesthesia and Pain Management, Medical University of Vienna, Währinger Gürtel 18-20, Vienna A-1090, Austria.
Anesthesiology
|August 23, 2008
Summary
A new genetic variant (W3985R) in the ryanodine receptor 1 is linked to malignant hyperthermia (MH) susceptibility. This finding enables genetic testing for families affected by this condition.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- Malignant hyperthermia (MH) is a genetic disorder causing a hypermetabolic state triggered by specific agents.
- Increased calcium (Ca) release from the sarcoplasmic reticulum is a key mechanism in MH.
- A novel ryanodine receptor 1 variant was identified in an Austrian family undergoing MH testing.
Purpose of the Study:
- To investigate the functional role of a newly identified ryanodine receptor 1 variant.
- To establish a link between this variant and susceptibility to malignant hyperthermia.
- To facilitate the application of genetic testing for MH in affected families.
Main Methods:
- Messenger RNA (mRNA) was isolated from cultured skeletal muscle cells for complementary DNA (cDNA) synthesis.
- Polymerase chain reactions (PCR) were performed, and all reaction products were sequenced.
- Functional studies involved measuring intracellular Ca concentration and Ca release in response to caffeine and 4-chloro-m-cresol, including voltage-dependence.
Main Results:
- A thymine to cysteine transition at position 11953 resulted in a tryptophan to arginine exchange at position 3985 (W3985R variant).
- This W3985R variant was not found in 100 non-susceptible individuals.
- Cells with the W3985R variant exhibited increased sensitivity to caffeine and 4-chloro-m-cresol and altered voltage-dependent Ca release.
Conclusions:
- The identified W3985R variant plays a role in malignant hyperthermia susceptibility.
- These functional data support the inclusion of this variant in genetic diagnostic testing for MH.
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