Kostera-Pruszczyk Anna, Suszek Małgorzata, Płoski Rafał, Franaszczyk Maria, Potulska-Chromik Anna, Pruszczyk Piotr, Sadurska Elżbieta, Karolczak Justyna, Kamińska Anna M, Rędowicz Maria Jolanta
Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097, Warsaw, Poland.
Department of Biochemistry, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093, Warsaw, Poland.
J Muscle Res Cell Motil. 2015 Dec;36(6):423-32. doi: 10.1007/s10974-015-9431-3. Epub 2015 Nov 6.
BAG3 belongs to BAG family of molecular chaperone regulators interacting with HSP70 and anti-apoptotic protein Bcl-2. It is ubiquitously expressed with strong expression in skeletal and cardiac muscle, and is involved in a panoply of cellular processes. Mutations in BAG3 and aberrations in its expression cause fulminant myopathies, presenting with progressive limb and axial muscle weakness, and respiratory insufficiency and neuropathy. Herein, we report a sporadic case of a 15-years old girl with symptoms of myopathy, demyelinating polyneuropathy and asymptomatic long QT syndrome. Genetic testing demonstrated heterozygous mutation Pro209Leu (c.626C > T) in exon 3 of BAG3 gene causing severe myopathy and neuropathy, often associated with restrictive cardiomyopathy. We did not find a mutation in any known LQT syndrome genes. Analysis of muscle biopsy revealed profound disintegration of Z-discs with extensive accumulation of granular debris and large inclusions within fibers. We demonstrated profound alterations in BAG3 distribution as the protein localized to long filamentous structures present across the fibers that were positively stained not only for α-actinin but also for desmin and filamin indicating that those disintegrated Z-disc regions contained also other sarcomeric proteins. The mutation caused a decrease in the content of BAG3 and HSP70, and also of α-actinin desmin, filamin and fast myosin heavy chain, confirming its severe effect on the muscle fiber morphology and thus function. We provide further evidence that BAG3 is associated with Z-disc maintenance, and the Pro209Leu mutation may occur worldwide. We also provide a summary of cases associated with this mutation reported so far.
BAG3属于与热休克蛋白70（HSP70）和抗凋亡蛋白Bcl-2相互作用的分子伴侣调节因子的BAG家族。它在全身广泛表达，在骨骼肌和心肌中表达强烈，并参与一系列细胞过程。BAG3的突变及其表达异常会导致暴发性肌病，表现为进行性肢体和躯干肌无力、呼吸功能不全和神经病变。在此，我们报告一例散发的15岁女孩病例，她有肌病、脱髓鞘性多发性神经病变症状以及无症状性长QT综合征。基因检测显示BAG3基因外显子3存在杂合突变Pro209Leu（c.626C>T），导致严重肌病和神经病变，常伴有限制性心肌病。我们在任何已知的长QT综合征基因中均未发现突变。肌肉活检分析显示Z盘严重解体，纤维内有大量颗粒碎片和大的包涵体堆积。我们证明BAG3分布发生了深刻改变，因为该蛋白定位于纤维中存在的长丝状结构，这些结构不仅对α-肌动蛋白呈阳性染色，对结蛋白和细丝蛋白也呈阳性染色，表明那些解体的Z盘区域还包含其他肌节蛋白。该突变导致BAG3和HSP70的含量降低，α-肌动蛋白、结蛋白、细丝蛋白和快肌球蛋白重链的含量也降低，证实了其对肌纤维形态及功能的严重影响。我们提供了进一步的证据表明BAG3与Z盘维持有关，Pro209Leu突变可能在全球范围内发生。我们还总结了迄今为止报道的与该突变相关的病例。
