Schirmer Ilona, Dieding Mareike, Klauke Bärbel, Brodehl Andreas, Gaertner-Rommel Anna, Walhorn Volker, Gummert Jan, Schulz Uwe, Paluszkiewicz Lech, Anselmetti Dario, Milting Hendrik
Erich and Hanna Klessmann Institute for Cardiovascular Research & Development (EHKI), Heart and Diabetes Centre NRW, University Hospital of the Ruhr-University Bochum, Bad Oeynhausen, Germany.
Faculty of Physics, Experimental Biophysics and Applied Nanoscience, Bielefeld Institute for Nanoscience (BINAS), Bielefeld University, Bielefeld, Germany.
Mol Genet Genomic Med. 2018 Mar;6(2):288-293. doi: 10.1002/mgg3.358. Epub 2017 Dec 23.
DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations.
Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a history of sudden cardiac death. We performed cell transfection experiments and in vitro assembly experiments to prove the pathogenicity of this novel DES indel mutation.
These experiments revealed a severe filament formation defect of mutant desmin supporting the pathogenicity. In addition, we labeled a skeletal muscle biopsy from the mutation carrier revealing cytoplasmic desmin positive protein aggregates. In summary, we identified and functionally characterized a pathogenic DES indel mutation causing cardiac and skeletal myopathy.
Our study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification.
结蛋白（DES）突变会导致不同的心脏和骨骼肌病。其中大多数是错义突变。
我们使用下一代测序心脏174基因检测板，在一名患有心肌病并伴有房室传导阻滞和骨骼肌病的白种人患者中，鉴定出一种新的杂合框内插入缺失突变（DES-c.493_520del28insGCGT，p.Q165_A174delinsAS）。该插入缺失突变位于第一个外显子的编码区。家族病史显示有心脏性猝死史。我们进行了细胞转染实验和体外组装实验，以证明这种新的DES插入缺失突变的致病性。
这些实验揭示了突变结蛋白存在严重的细丝形成缺陷，支持了其致病性。此外，我们对来自突变携带者的骨骼肌活检样本进行标记，发现胞质结蛋白阳性蛋白聚集体。总之，我们鉴定并从功能上表征了一种导致心脏和骨骼肌病的致病性DES插入缺失突变。
我们的研究对于进一步导致心脏或骨骼肌病的DES插入缺失突变的临床和遗传学解释具有重要意义，可能有助于风险分层。
