Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility.
Identifieur interne : 000155 ( Canada/Analysis ); précédent : 000154; suivant : 000156Exome analysis identifies Brody myopathy in a family diagnosed with malignant hyperthermia susceptibility.
Auteurs : Nyamkhishig Sambuughin [États-Unis] ; Elena Zvaritch [Canada] ; Natasha Kraeva [Canada] ; Olga Sizova [Canada] ; Erica Sivak [États-Unis] ; Kelley Dickson [États-Unis] ; Margaret Weglinski [États-Unis] ; John Capacchione [États-Unis] ; Sheila Muldoon [États-Unis] ; Sheila Riazi [Canada] ; Susan Hamilton [États-Unis] ; Barbara Brandom [États-Unis] ; David H. Maclennan [Canada]Source :
- Molecular genetics & genomic medicine [ 2324-9269 ] ; 2014.
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.
DOI: 10.1002/mgg3.91
PubMed: 25614869
Affiliations:
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Bethesda, Maryland.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Department of Anesthesiology, Uniformed Services University Bethesda</wicri:cityArea></affiliation></author><author><name sortKey="Riazi, Sheila" sort="Riazi, Sheila" uniqKey="Riazi S" first="Sheila" last="Riazi">Sheila Riazi</name><affiliation wicri:level="1"><nlm:affiliation>Department of Anesthesia, Toronto General Hospital Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Department of Anesthesia, Toronto General Hospital Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Hamilton, Susan" sort="Hamilton, Susan" uniqKey="Hamilton S" first="Susan" last="Hamilton">Susan Hamilton</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, Texas.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston</wicri:cityArea></affiliation></author><author><name sortKey="Brandom, Barbara" sort="Brandom, Barbara" uniqKey="Brandom B" first="Barbara" last="Brandom">Barbara Brandom</name><affiliation wicri:level="2"><nlm:affiliation>Department of Anesthesiology, Children's Hospital, University of Pittsburgh Pittsburgh, Pennsylvania.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>Department of Anesthesiology, Children's Hospital, University of Pittsburgh Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Maclennan, David H" sort="Maclennan, David H" uniqKey="Maclennan D" first="David H" last="Maclennan">David H. Maclennan</name><affiliation wicri:level="1"><nlm:affiliation>Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author></analytic><series><title level="j">Molecular genetics & genomic medicine</title><idno type="ISSN">2324-9269</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Maryland</li><li>Minnesota</li><li>Pennsylvanie</li><li>Texas</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Sambuughin, Nyamkhishig" sort="Sambuughin, Nyamkhishig" uniqKey="Sambuughin N" first="Nyamkhishig" last="Sambuughin">Nyamkhishig Sambuughin</name></region><name sortKey="Brandom, Barbara" sort="Brandom, Barbara" uniqKey="Brandom B" first="Barbara" last="Brandom">Barbara Brandom</name><name sortKey="Capacchione, John" sort="Capacchione, John" uniqKey="Capacchione J" first="John" last="Capacchione">John Capacchione</name><name sortKey="Dickson, Kelley" sort="Dickson, Kelley" uniqKey="Dickson K" first="Kelley" last="Dickson">Kelley Dickson</name><name sortKey="Hamilton, Susan" sort="Hamilton, Susan" uniqKey="Hamilton S" first="Susan" last="Hamilton">Susan Hamilton</name><name sortKey="Muldoon, Sheila" sort="Muldoon, Sheila" uniqKey="Muldoon S" first="Sheila" last="Muldoon">Sheila Muldoon</name><name sortKey="Sivak, Erica" sort="Sivak, Erica" uniqKey="Sivak E" first="Erica" last="Sivak">Erica Sivak</name><name sortKey="Weglinski, Margaret" sort="Weglinski, Margaret" uniqKey="Weglinski M" first="Margaret" last="Weglinski">Margaret Weglinski</name></country><country name="Canada"><noRegion><name sortKey="Zvaritch, Elena" sort="Zvaritch, Elena" uniqKey="Zvaritch E" first="Elena" last="Zvaritch">Elena Zvaritch</name></noRegion><name sortKey="Kraeva, Natasha" sort="Kraeva, Natasha" uniqKey="Kraeva N" first="Natasha" last="Kraeva">Natasha Kraeva</name><name sortKey="Maclennan, David H" sort="Maclennan, David H" uniqKey="Maclennan D" first="David H" last="Maclennan">David H. Maclennan</name><name sortKey="Riazi, Sheila" sort="Riazi, Sheila" uniqKey="Riazi S" first="Sheila" last="Riazi">Sheila Riazi</name><name sortKey="Sizova, Olga" sort="Sizova, Olga" uniqKey="Sizova O" first="Olga" last="Sizova">Olga Sizova</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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