title: Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility.
abstract: Whole exome sequencing (WES) was used to determine the primary cause of muscle disorder in a family diagnosed with a mild, undetermined myopathy and malignant hyperthermia (MH) susceptibility (MHS). WES revealed the compound heterozygous mutations, p.Ile235Asn and p.Glu982Lys, in ATP2A1, encoding the sarco(endo)plasmic reticulum Ca(2+) ATPase type 1 (SERCA1), a calcium pump, expressed in fast-twitch muscles. Recessive mutations in ATP2A1 are known to cause Brody myopathy, a rare muscle disorder characterized by exercise-induced impairment of muscle relaxation and stiffness. Analyses of affected muscles showed the absence of SERCA1, but SERCA2 upregulation in slow and fast myofibers, suggesting a compensatory mechanism that partially restores the diminished Ca(2+) transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca(2+) pumping activity within the muscle explains, in part, the mild course of disease in our patient. Diagnosis of MHS in this family was secondary to a loss of SERCA1 due to disease-associated mutations. Although there are obvious differences in clinical expression and molecular mechanisms between MH and Brody myopathy, a feature common to both conditions is elevated myoplasmic Ca(2+) content. Prolonged intracellular Ca(2+) elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.
authors.affiliation: Defense and Veterans Center for Integrated Pain Management, Henry M. Jackson Foundation Rockville, Maryland ; Department of Anesthesiology, Uniformed Services University Bethesda, Maryland.
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Zvaritch
authors.affiliation: Department of Anesthesia, Toronto General Hospital Toronto, Ontario, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Kraeva
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Sizova
authors.affiliation: Department of Anesthesiology, Children's Hospital, University of Pittsburgh Pittsburgh, Pennsylvania.
authors.forename: Erica
authors.initials: E
authors.lastname: Sivak
authors.affiliation: Department of Anesthesiology, Uniformed Services University Bethesda, Maryland.
authors.forename: Kelley
authors.initials: K
authors.lastname: Dickson
authors.affiliation: Department of Anesthesiology, Mayo Clinic Rochester, Minnesota.
authors.forename: Margaret
authors.initials: M
authors.lastname: Weglinski
authors.affiliation: Department of Anesthesiology, Uniformed Services University Bethesda, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Capacchione
authors.affiliation: Department of Anesthesiology, Uniformed Services University Bethesda, Maryland.
authors.forename: Sheila
authors.initials: S
authors.lastname: Muldoon
authors.affiliation: Department of Anesthesia, Toronto General Hospital Toronto, Ontario, Canada.
authors.forename: Sheila
authors.initials: S
authors.lastname: Riazi
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, Texas.
authors.forename: Susan
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Department of Anesthesiology, Children's Hospital, University of Pittsburgh Pittsburgh, Pennsylvania.
authors.forename: Barbara
authors.initials: B
authors.lastname: Brandom
authors.affiliation: Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.
authors.forename: David H
authors.initials: DH
authors.lastname: MacLennan
keywords: Brody myopathy; RYR1; SERCA1; malignant hyperthermia