Exome analysis identifies brody myopathy in a family diagnosed with malignant hyperthermia susceptibility

Nyamkhishig Sambuughin, Elena Zvaritch, Natasha Kraeva, Olga Sizova, Erica Sivak, Kelley Dickson, Margaret Weglinski, John Capacchione, Sheila Muldoon, Sheila Riazi, Susan Hamilton, Barbara Brandom, David H. Maclennan

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12 Scopus citations


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 Ca2+ 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 Ca2+ transport in Brody myopathy. This compensatory adaptation to the lack of SERCA1 Ca2+ 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 Ca2+ content. Prolonged intracellular Ca2+ elevation is likely to have led to MHS diagnosis in vitro and postoperative MH-like symptoms in Brody patient.

Original languageEnglish (US)
Pages (from-to)472-483
Number of pages12
JournalMolecular Genetics and Genomic Medicine
Issue number6
StatePublished - Nov 2014

Bibliographical note

Publisher Copyright:
© 2014 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.


  • Brody myopathy
  • Malignant hyperthermia
  • RYR1
  • SERCA1


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