title: A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias.
abstract: Dilated cardiomyopathy (DCM) is the most prevalent type of primary myocardial disease, which is the third most common cause of heart failure and the most frequent reason for heart transplantation. Aggregating evidence demonstrates that genetic risk factors are involved in the pathogenesis of idiopathic DCM. Nevertheless, DCM is of remarkable genetic heterogeneity and the genetic defects underpinning DCM in an overwhelming majority of patients remain unknown. In the present study, the whole coding exons and splice junction sites of the NKX2-5 gene, which encodes a homeodomain transcription factor crucial for cardiac development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for the NKX2-5 gene. The functional effect of the mutant NKX2-5 was characterized in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2-5 mutation, p.S146W, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. Notably, the mutation carriers also had arrhythmias, such as paroxysmal atrial fibrillation and atrioventricular block. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the NKX2-5 mutant was associated with a significantly reduced transcriptional activity. The findings expand the mutational spectrum of NKX2-5 linked to DCM and provide novel insight into the molecular mechanisms underlying DCM, contributing to the antenatal prophylaxis and allele-specific management of DCM.
authors.affiliation: Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yuan
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xing-Biao
authors.initials: XB
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ruo-Gu
authors.initials: RG
authors.lastname: Li
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xin-Kai
authors.initials: XK
authors.lastname: Qu
authors.affiliation: Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Ying-Jia
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Fang
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China.
authors.forename: De-Ning
authors.initials: DN
authors.lastname: Liao
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D014157:Transcription Factors