Sambuughin Nyamkhishig, Zvaritch Elena, Kraeva Natasha, Sizova Olga, Sivak Erica, Dickson Kelley, Weglinski Margaret, Capacchione John, Muldoon Sheila, Riazi Sheila, Hamilton Susan, Brandom Barbara, MacLennan David H
Defense and Veterans Center for Integrated Pain Management, Henry M. Jackson Foundation Rockville, Maryland ; Department of Anesthesiology, Uniformed Services University Bethesda, Maryland.
Banting and Best Department of Medical Research, University of Toronto Toronto, Ontario, Canada.
Mol Genet Genomic Med. 2014 Nov;2(6):472-83. doi: 10.1002/mgg3.91. Epub 2014 Jun 6.
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.
全外显子组测序（WES）用于确定一个被诊断患有轻度、未明确的肌病和恶性高热（MH）易感性（MHS）的家族中肌肉疾病的主要病因。WES揭示了ATP2A1基因中的复合杂合突变，即p.Ile235Asn和p.Glu982Lys，该基因编码肌浆（内质）网钙（2+）ATP酶1型（SERCA1），一种钙泵，在快肌中表达。已知ATP2A1中的隐性突变会导致布罗迪肌病，这是一种罕见的肌肉疾病，其特征是运动诱导的肌肉松弛受损和僵硬。对受影响肌肉的分析显示SERCA1缺失，但慢肌纤维和快肌纤维中SERCA2上调，提示存在一种补偿机制，可部分恢复布罗迪肌病中减少的钙（2+）转运。这种对肌肉内SERCA1钙泵活性缺乏的代偿性适应，部分解释了我们患者疾病的轻度病程。该家族中MHS的诊断继发于与疾病相关的突变导致的SERCA1缺失。尽管MH和布罗迪肌病在临床表型和分子机制上存在明显差异，但这两种疾病的一个共同特征是肌浆钙（2+）含量升高。细胞内钙（2+）长时间升高可能导致了体外MHS诊断以及布罗迪病患者术后出现类似MH的症状。
