Functional characterization of the RYR1 mutation p.Arg4737Trp associated with susceptibility to malignant hyperthermia

Autor: Clemens R. Müller, Norbert Roewer, Susan Treves, Stephan Johannsen, Daniel Schneiderbanger, Susanne Mögele, Frank Schuster
Rok vydání: 2015
Předmět:
Male
Phosphodiesterase Inhibitors
caratterizzazione funzionale
Calcium in biology
Cresols
0302 clinical medicine
030202 anesthesiology
Germany
ipertermia maligna
Genetics (clinical)
Cell Line
Transformed
B-Lymphocytes
Ryanodine receptor
Malignant hyperthermia
Tryptophan
musculoskeletal system
Neurology
Mutation (genetic algorithm)
Female
mutazioni
Halothane
Intracellular
Muscle Contraction
medicine.medical_specialty
mutazioni
ipertermia maligna
caratterizzazione funzionale
chemistry.chemical_element
Calcium
Biology
Arginine
Polymorphism
Single Nucleotide
NO
03 medical and health sciences
Internal medicine
Caffeine
medicine
Humans
Genetic Predisposition to Disease
Muscle
Skeletal
Anesthetics
RYR1
Family Health
Wild type
Ryanodine Receptor Calcium Release Channel
medicine.disease
Molecular biology
Fungicides
Industrial
Endocrinology
chemistry
Pediatrics
Perinatology and Child Health
Neurology (clinical)
Malignant Hyperthermia
030217 neurology & neurosurgery
Zdroj: Neuromuscular disorders : NMD. 26(1)
ISSN: 1873-2364
Popis: Aside from the in vitro contracture test, genetic screening for causative RYR1 mutations is the established procedure to diagnose susceptibility to malignant hyperthermia (MH). However, currently only 34 out of more than 300 known RYR1 mutations have been confirmed to be causative for MH by experimental studies addressing their functional impact on intracellular calcium homeostasis. The RYR1 mutation p.Arg4737Trp has been recently detected in a German MH family. To evaluate the effects of that mutation on intracellular calcium handling, the response after stimulation with the RYR1 agonist 4-chloro-m-cresol was investigated in immortalized B lymphocytes containing the p.Arg4737Trp mutation and compared to the response of wild type RYR1 from unaffected family members and unrelated controls. Intracellular resting calcium was slightly but significantly elevated in mutation positive cells. Calcium release following stimulation with 4-chloro-m-cresol was significantly increased in B lymphocytes carrying the p.Arg4737Trp mutation compared to mutation negative controls. Hence, the functional properties of the RYR1 mutation p.Arg4737Trp are consistent with susceptibility to MH. Together with previously published data, the mutation has now been reported in three independent MH positive families.
Databáze: OpenAIRE
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