Perrot Andreas, Tomasov Pavol, Villard Eric, Faludi Reka, Melacini Paola, Lossie Janine, Lohmann Nadine, Richard Pascale, De Bortoli Marzia, Angelini Annalisa, Varga-Szemes Akos, Sperling Silke R, Simor Tamás, Veselka Josef, Özcelik Cemil, Charron Philippe
Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany.
Department of Cardiology, 2 Medical School, Charles University, University Hospital Motol, Prague, Czech Republic.
Arch Med Sci. 2016 Apr 1;12(2):263-78. doi: 10.5114/aoms.2016.59250. Epub 2016 Apr 11.
Transgenic mice overexpressing mutated NEBL, encoding the cardiac-specific Z-disk protein nebulette, develop severe cardiac phenotypes. Since cardiomyopathies are commonly familial and because mutations in a single gene may result in variable phenotypes, we tested the hypothesis that NEBL mutations are associated with cardiomyopathy.
We analyzed 389 patients, including cohorts of patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and left ventricular non-compaction cardiomyopathy (LVNC). The 28 coding exons of the NEBL gene were sequenced. Further bioinformatic analysis was used to distinguish variants.
In total, we identified six very rare heterozygous missense mutations in NEBL in 7 different patients (frequency 1.8%) in highly conserved codons. The mutations were not detectable in 320 Caucasian sex-matched unrelated individuals without cardiomyopathy and 192 Caucasian sex-matched blood donors without heart disease. Known cardiomyopathy genes were excluded in these patients. The mutations p.H171R and p.I652L were found in 2 HCM patients. Further, p.Q581R and p.S747L were detected in 2 DCM patients, while the mutation p.A175T was identified independently in two unrelated patients with DCM. One LVNC patient carried the mutation p.P916L. All HCM and DCM related mutations were located in the nebulin-like repeats, domains responsible for actin binding. Interestingly, the mutation associated with LVNC was located in the C-terminal serine-rich linker region.
Our data suggest that NEBL mutations may cause various cardiomyopathies. We herein describe the first NEBL mutations in HCM and LVNC. Our findings underline the notion that the cardiomyopathies are true allelic diseases.
过度表达突变型NEBL（编码心脏特异性Z盘蛋白nebulin）的转基因小鼠会出现严重的心脏表型。由于心肌病通常具有家族性，且单个基因的突变可能导致多种表型，我们检验了NEBL突变与心肌病相关的假说。
我们分析了389例患者，包括扩张型心肌病（DCM）、肥厚型心肌病（HCM）和左心室致密化不全心肌病（LVNC）患者队列。对NEBL基因的28个编码外显子进行了测序。进一步的生物信息学分析用于区分变异体。
我们总共在7名不同患者中鉴定出NEBL基因的6个非常罕见的杂合错义突变（频率为1.8%），这些突变位于高度保守的密码子中。在320名无心肌病的白种人性别匹配无关个体和192名无心脏病的白种人性别匹配献血者中未检测到这些突变。这些患者排除了已知的心肌病基因。在2例HCM患者中发现了p.H171R和p.I652L突变。此外，在2例DCM患者中检测到p.Q581R和p.S747L突变，而p.A175T突变在两名无关的DCM患者中独立发现。1例LVNC患者携带p.P916L突变。所有与HCM和DCM相关的突变都位于nebulin样重复序列中，该区域负责肌动蛋白结合。有趣的是，与LVNC相关的突变位于C末端富含丝氨酸的连接区。
我们的数据表明NEBL突变可能导致多种心肌病。我们在此描述了HCM和LVNC中的首个NEBL突变。我们的发现强调了心肌病是真正的等位基因疾病这一观点。
