title: A novel lamin A/C gene missense mutation (445 V > E) in immunoglobulin-like fold associated with left ventricular non-compaction.
abstract: Two LMNA mutations (R644C and R190W) have been associated with familial and sporadic left ventricular non-compaction (LVNC). However, the mechanisms underlying these associations have not been elucidated.
  
  
  
  Genomic DNA was isolated from peripheral blood leucocytes and analysed by direct sequencing. Human embryonic kidney 293 cells were transfected with either wild type or mutant LMNA and SCN5A for whole-cell patch-clamp experiment and fluorescence microscopy. Point mutation modeling for mutant LMNA was also performed. One novel LVNC-associated mutation (V445E) in β2 sheet of immunoglobulin (Ig)-like fold was found in the proband and his father. We also found that the peak current of sodium channel was markedly reduced in mutant LMNA compared with WT while the activation, inactivation, and recovery curves were not significantly altered. The mutant lamin A/C were aggregated into multiple highlighted particles. Three β sheets and multiple side chains in Ig-like fold were altered due to the replacement of a valine by glutamic acid.
  
  
  
  Our data associated a novel lamin A/C mutation (V445E) with a sudden death form of familial LVNC. The reduced sodium current in mutant LMNA may account for the advent of malignant ventricular arrhythmias. The altered structures of three β sheets and side chains may partially explain the aggregation of lamin A/C protein subjacent to the nuclear envelope.
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Physiology and Pathophysiology Laboratory, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei-Li-Shi Road, Xi-Cheng District, Beijing 100037, P.R. China.
authors.forename: Zhouying
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biophysics, School of Basic Medical Sciences, Peking University, 38 Xue-Yuan Road, Hai-Dian District, Beijing 100191, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Shan
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Physiology and Pathophysiology Laboratory, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei-Li-Shi Road, Xi-Cheng District, Beijing 100037, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Physiology and Pathophysiology Laboratory, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei-Li-Shi Road, Xi-Cheng District, Beijing 100037, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Physiology and Pathophysiology Laboratory, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei-Li-Shi Road, Xi-Cheng District, Beijing 100037, P.R. China jielinpu@yahoo.com houch1968@sohu.com.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Hou
authors.affiliation: State Key Laboratory of Cardiovascular Disease, Physiology and Pathophysiology Laboratory, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Bei-Li-Shi Road, Xi-Cheng District, Beijing 100037, P.R. China jielinpu@yahoo.com houch1968@sohu.com.
authors.forename: Jielin
authors.initials: J
authors.lastname: Pu
mesh_terms: D000293:Adolescent; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D004452:Echocardiography; D004562:Electrocardiography; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D056830:Isolated Noncompaction of the Ventricular Myocardium / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010641:Phenotype; D066329:Protein Aggregates; D000072757:Protein Conformation, beta-Strand; D017510:Protein Folding; D013329:Structure-Activity Relationship; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014162:Transfection; D014633:Valine; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D055815:Young Adult
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D066329:Protein Aggregates; D018698:Glutamic Acid; D014633:Valine
keywords: LMNA mutation; Left ventricular non-compaction; Sodium channel; Sudden death