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Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
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Functional characterization of 2 known ryanodine receptor mutations causing malignant hyperthermia
Anja H Schiemann1, Neeti Paul, Remai Parker
1From the Institute of Fundamental Sciences, Massey University; and Department of Anaesthesia and Intensive Care, MidCentral Health, Palmerston North Hospital, Palmerston North, New Zealand.
Anesthesia and Analgesia
|December 24, 2013
Summary
Malignant hyperthermia (MH) is a severe disorder. This study confirms R2355W as an MH-causing RYR1 mutation and suggests V2354M is also causative, aiding MH diagnosis.
Area of Science:
- Genetics
- Pharmacology
- Cell Biology
Background:
- Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder.
- Over 300 ryanodine receptor 1 (RYR1) variants are linked to MH, but only 31 are confirmed causative.
- Confirmation requires family segregation and functional assays demonstrating abnormal calcium release.
Purpose of the Study:
- To identify and confirm causative RYR1 mutations in New Zealand families with MH susceptibility.
- To investigate the functional impact of identified RYR1 variants on calcium release.
Main Methods:
- "Hot-spot" DNA screening was employed to detect RYR1 mutations in three New Zealand families.
- B-lymphoblastoid cells were utilized to compare calcium release in response to 4-chloro-m-cresol between wild-type and mutant RYR1 cells.
Main Results:
- A known RYR1 mutation (R2355W) was identified in two families, and a recently identified mutation (V2354M) was found in another.
- Both identified mutations segregated with MH susceptibility within their respective families.
- RYR1 mutation-carrying cell lines exhibited heightened sensitivity to 4-chloro-m-cresol stimulation.
Conclusions:
- The RYR1 R2355W mutation is confirmed as causative for malignant hyperthermia.
- The RYR1 V2354M mutation is proposed as a likely causative mutation for MH.
- These findings contribute to the genetic understanding and diagnosis of MH.
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