Related Experiment Video
Updated: Aug 23, 2025
Functional Characterization of Endogenously Expressed Human RYR1 Variants
Published on: June 9, 2021
Gene Panel Sequencing Identifies a Novel RYR1 p.Ser2300Pro Variant as Candidate for Malignant Hyperthermia with
Young Jae Moon1,2, Joonhong Park3,4, Jung Ryul Kim1
1Department of Orthopedic Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea.
Abstract:
Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Ca2+ release testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a novel RYR1 heterozygous missense variant (NM_000540.2: c.6898T > C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Ca2+ release testing in B lymphocytes showed hypersensitive Ca2+ responses to isoflurane and caffeine, resulting in an abnormal Ca2+ release only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.
Insights
Malignant hyperthermia (MH) is a rare disorder triggered by sevoflurane. This study details a Korean patient with MH and multi-minicore myopathy, linked to a novel RYR1 gene variant and abnormal calcium release.
Area of Science:
- Pharmacogenetics
- Muscle Physiology
- Calcium Signaling
Background:
- Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder affecting skeletal muscle calcium regulation.
- Sevoflurane is a known trigger for MH in susceptible individuals.
- Multi-minicore myopathy is a rare congenital muscle disorder.
Observation:
- A 14-year-old Korean male presented with progressive torticollis, scoliosis, and flexion contractures.
- During general anesthesia, the patient exhibited symptoms consistent with MH, which were successfully treated with dantrolene.
- Genetic analysis revealed a novel RYR1 heterozygous missense variant (c.6898T > C; p.Ser2300Pro) in the MH2 domain.
Findings:
- Ex vivo testing demonstrated hypersensitive intracellular Ca2+ release in B lymphocytes upon exposure to isoflurane and caffeine, confirming RYR1-mediated dysfunction.
- The identified RYR1 variant is located in a known mutation hotspot for MH.
- The abnormal Ca2+ release was specific to the proband, not observed in family members.
Implications:
- This case expands the known clinical and pathological spectrum of MH associated with multi-minicore myopathy.
- The findings highlight the utility of RYR1-mediated intracellular Ca2+ release testing in B lymphocytes for diagnosing MH.
- Understanding novel RYR1 variants contributes to improved genetic counseling and anesthetic management for patients with muscle disorders.
