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.

AP HP Département de Génétique et Département de Cardiologie et Inserm UMR 1166 Hopital Pitié Salpêtrière Paris France

AP HP Département de Génétique et Département de Cardiologie et Inserm UMR 1166 Hopital Pitié Salpêtrière Paris France; Université de Versailles Saint Quentin en Yvelines Versailles France

Assistance Publique Hôpitaux de Paris Groupe Hospitalier Pitié Salpêtrière UF Cardiogénétique et Myogénétique Service de Biochimie Métabolique Paris France

Charité Universitätsmedizin Berlin Cardiovascular Genetics Experimental and Clinical Research Center Berlin Germany

Charité Universitätsmedizin Berlin Cardiovascular Genetics Experimental and Clinical Research Center Berlin Germany; Knappschaftskrankenhaus Recklinghausen Medizinischen Klinik 1 Kardiologie Gastroenterologie und Diabetologie Recklinghausen Germany

Department of Cardiac Thoracic and Vascular Sciences University of Padova Padova Italy

Department of Cardiology 2 Medical School Charles University University Hospital Motol Prague Czech Republic

Heart Institute Faculty of Medicine University of Pécs Pécs Hungary

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