title: Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.
abstract: Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.
authors.affiliation: Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Forleo
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Carmosino
authors.affiliation: Section of Medical Genetics, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rampazzo
authors.affiliation: Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Valecce
authors.affiliation: Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorrentino
authors.affiliation: Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacoviello
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procino
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerbino
authors.affiliation: Section of Radiology, Interdisciplinary Department of Medicine, University of Bari, Bari, Italy.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Scardapane
authors.affiliation: Section of Medical Genetics, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
authors.affiliation: Department of Biology, University of Padua, Padua, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Calore
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Torretta
authors.affiliation: Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, Bari, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.affiliation: Cardiology Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Favale
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000473:pathology; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006329:Heart Conduction System / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D019683:Penetrance; D061251:Primary Cell Culture; D016415:Sequence Alignment
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A
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