Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies

Andreas Perrot, Pavol Tomasov, Eric Villard, Reka Faludi, Paola Melacini, Janine Lossie, Nadine Lohmann, Pascale Richard, Marzia De Bortoli, Annalisa Angelini, Akos Varga-Szemes, Silke R. Sperling, Tamás Simor, Josef Veselka, Cemil Özcelik, Philippe Charron

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Introduction: 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. Material and methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)263-278
Number of pages16
JournalArchives of Medical Science
Issue number2
Publication statusPublished - Apr 2016


  • Cardiomyopathy
  • Dilated
  • Genetics
  • Hypertrophic
  • Non-compaction

ASJC Scopus subject areas

  • Medicine(all)

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    Perrot, A., Tomasov, P., Villard, E., Faludi, R., Melacini, P., Lossie, J., Lohmann, N., Richard, P., De Bortoli, M., Angelini, A., Varga-Szemes, A., Sperling, S. R., Simor, T., Veselka, J., Özcelik, C., & Charron, P. (2016). Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies. Archives of Medical Science, 12(2), 263-278.