title: Mutations in NEBL encoding the cardiac Z-disk protein nebulette are associated with various cardiomyopathies.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.affiliation: Department of Cardiology, 2 Medical School, Charles University, University Hospital Motol, Prague, Czech Republic.
authors.forename: Pavol
authors.initials: P
authors.lastname: Tomasov
authors.affiliation: AP-HP, Département de Génétique et Département de Cardiologie et Inserm UMR 1166, Hopital Pitié-Salpêtrière, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Villard
authors.affiliation: Heart Institute, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Reka
authors.initials: R
authors.lastname: Faludi
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Melacini
authors.affiliation: Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Lossie
authors.affiliation: Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Lohmann
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: De Bortoli
authors.affiliation: Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
authors.affiliation: Heart Institute, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Akos
authors.initials: A
authors.lastname: Varga-Szemes
authors.affiliation: Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany.
authors.forename: Silke R
authors.initials: SR
authors.lastname: Sperling
authors.affiliation: Heart Institute, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Simor
authors.affiliation: Department of Cardiology, 2 Medical School, Charles University, University Hospital Motol, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Veselka
authors.affiliation: Charité-Universitätsmedizin Berlin, Cardiovascular Genetics, Experimental and Clinical Research Center, Berlin, Germany; Knappschaftskrankenhaus Recklinghausen, Medizinischen Klinik I Kardiologie, Gastroenterologie und Diabetologie, Recklinghausen, Germany.
authors.forename: Cemil
authors.initials: C
authors.lastname: Özcelik
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
keywords: cardiomyopathy; dilated; genetics; hypertrophic; non-compaction