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Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Assessing the pathogenicity of RYR1 variants in malignant hyperthermia
A Merritt1, P Booms1, M-A Shaw1
1Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
British Journal of Anaesthesia
|April 14, 2017
Summary
Functional assays in HEK293 cells help identify pathogenic RYR1 variants for malignant hyperthermia diagnosis. Five RYR1 variants (p.R2336H, p.R2355W, p.E3104K, p.G3990V, p.V4849I) are recommended for diagnostic use.
Area of Science:
- Genetics
- Molecular Biology
- Pharmacology
Background:
- Missense variants in the ryanodine receptor 1 gene (RYR1) are linked to malignant hyperthermia.
- Few RYR1 variants meet criteria for predictive DNA diagnosis of malignant hyperthermia.
Purpose of the Study:
- To assess the utility of simplified segregation analysis and functional assays for determining RYR1 variant pathogenicity.
- To evaluate recurrent RYR1 variants associated with malignant hyperthermia.
Main Methods:
- Identified RYR1 variants in at least four malignant hyperthermia families.
- Performed simplified segregation analyses.
- Expressed RYR1 variants in HEK293 cells and measured caffeine-induced calcium release.
Main Results:
- Identified 43 families with six RYR1 variants; genotype segregated with phenotype for p.E3104K and p.D3986E, but with limited statistical significance.
- HEK293 functional assays showed increased RyR1 channel sensitivity for p.R2336H, p.R2355W, p.E3104K, p.G3990V, and p.V4849I.
- Cells expressing p.D3986E showed similar caffeine sensitivity to wild type RyR1.
Conclusions:
- Segregation analysis has limited value for assessing RYR1 variant pathogenicity in malignant hyperthermia.
- Functional assays support the diagnostic use of p.R2336H, p.R2355W, p.E3104K, p.G3990V, and p.V4849I.
- p.D3986E is not recommended for diagnostic use based on current functional data.
