Functional Characterization of C-terminal Ryanodine Receptor 1 Variants Associated with Central Core Disease or Malignant Hyperthermia.

Abstract

BACKGROUND:

Central core disease and malignant hyperthermia are human disorders of skeletal muscle resulting from aberrant Ca2+ handling. Most malignant hyperthermia and central core disease cases are associated with amino acid changes in the type 1 ryanodine receptor (RyR1), the skeletal muscle Ca2+-release channel. Malignant hyperthermia exhibits a gain-of-function phenotype, and central core disease results from loss of channel function. For a variant to be classified as pathogenic, functional studies must demonstrate a correlation with the pathophysiology of malignant hyperthermia or central core disease.

OBJECTIVE:

We assessed the pathogenicity of four C-terminal variants of the ryanodine receptor using functional analysis. The variants were identified in families affected by either malignant hyperthermia or central core disease.

METHODS:

Four variants were introduced separately into human cDNA encoding the skeletal muscle ryanodine receptor. Following transient expression in HEK-293T cells, functional studies were carried out using calcium release assays in response to an agonist. Two previously characterized variants and wild-type skeletal muscle ryanodine receptor were used as controls.

RESULTS:

The p.Met4640Ile variant associated with central core disease showed no difference in calcium release compared to wild-type. The p.Val4849Ile variant associated with malignant hyperthermia was more sensitive to agonist than wild-type but did not reach statistical significance and two variants (p.Phe4857Ser and p.Asp4918Asn) associated with central core disease were completely inactive.

CONCLUSIONS:

The p.Val4849Ile variant should be considered a risk factor for malignant hyperthermia, while the p.Phe4857Ser and p.Asp4918Asn variants should be classified as pathogenic for central core disease.

• Authors: Remai Parker, Anja H Schiemann, Elaine Langton, Terasa Bulger, Neil Pollock, Andrew Bjorksten, Robyn Gillies, David Hutchinson, Richard Roxburgh, Kathryn M Stowell
• Journal: Journal of neuromuscular diseases (J Neuromuscul Dis) 2017 Vol. 4 Issue 2 Pg. 147-158 ISSN: 2214-3599 [Print] Netherlands
• PMID: 28527222 (Publication Type: Case Reports, Journal Article)

Chemical References

• RYR1 protein, human
• Ryanodine Receptor Calcium Release Channel
• Calcium

Topics

• Adult
• Aged
• Calcium (metabolism)
• Family
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• HEK293 Cells
• Humans
• Male
• Malignant Hyperthermia (genetics, metabolism, therapy)
• Middle Aged
• Mutagenesis, Site-Directed
• Myopathy, Central Core (genetics, metabolism, therapy)
• Pedigree
• Ryanodine Receptor Calcium Release Channel (genetics, metabolism)