title: Novel excitation-contraction uncoupled RYR1 mutations in patients with central core disease.
abstract: Central core disease, one of the most common congenital myopathies in humans, has been linked to mutations in the RYR1 gene encoding the Ca(2+) release channel of the sarcoplasmic reticulum (RyR1). Functional analyses showed that disease-associated RYR1 mutations led to impairment of skeletal muscle Ca(2+) homeostasis; however, thorough understanding of the molecular mechanisms underlying central core disease and other RyR1-related conditions is still lacking. We screened by sequencing the complete RYR1 transcripts in ten unrelated patients with central core disease and identified five novel, p.M4640R, p.L4647P, p.F4808L, p.D4918N and p.F4941C, and four recurrent mutations. Four of the novel mutations involved amino acid residues that were positioned within putative transmembrane segments of the RyR1. The pathogenic character of the identified mutations was demonstrated by bioinformatic analyses and by the in vitro functional studies in HEK293 cells and RYR1-null (dyspedic) myotubes. Characterization of Ca(2+) channel properties of RyR1s carrying one recurrent and two novel mutations upholds the view that diminished intracellular Ca(2+) release caused by impaired Ca(2+) channel gating and/or Ca(2+) permeability is an important component of central core disease etiology. This study expands the list of functionally characterized disease-associated RyR1 mutations, increasing the value of genetic diagnosis for RyR1-related disorders.
authors.affiliation: Malignant Hyperthermia Investigation Unit, Toronto General Hospital, University Health Network, Toronto, ON, Canada M5G 2C4.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kraeva
authors.forename: Elena
authors.initials: E
authors.lastname: Zvaritch
authors.forename: Ann E
authors.initials: AE
authors.lastname: Rossi
authors.forename: Sanjeewa A
authors.initials: SA
authors.lastname: Goonasekera
authors.forename: Hilal
authors.initials: H
authors.lastname: Zaid
authors.forename: Wanda
authors.initials: W
authors.lastname: Frodis
authors.forename: Alexander
authors.initials: A
authors.lastname: Kraev
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: David H
authors.initials: DH
authors.lastname: Maclennan
authors.forename: Sheila
authors.initials: S
authors.lastname: Riazi
mesh_terms: D000293:Adolescent; D000328:Adult; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005820:Genetic Testing; D057809:HEK293 Cells; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020512:Myopathy, Central Core / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium