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Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy
- Source :
- European journal of medical genetics. 63(4)
- Publication Year :
- 2019
-
Abstract
- As a prevalent primary myocardial disease, dilated cardiomyopathy (DCM) represents the most common cause of heart failure in the young and the most frequent indication for cardiac transplantation. Aggregating evidence highlights the genetic basis of DCM. However, due to substantial genetic heterogeneity, the genetic defects of DCM in most cases remain elusive. In the current investigation, the entire coding exons and splicing junctions of the KLF5 gene, which encodes a key transcription factor required for cardiac structural and functional remodeling, were sequenced in 234 probands affected with DCM, and a heterozygous KLF5 mutation, NM_001730.5: c.1100T > A; p.(Leu367*), was identified in a proband. Genetic analysis of the proband's family members revealed that the identified KLF5 mutation co-segregated with DCM in the family with complete penetrance. The nonsense mutation was neither detected in 506 control individuals nor reported in such population-genetics databases as ExAC, dbSNP and gnomAD. Biological assays with a dual-luciferase reporter assay system demonstrated that the mutant KLF5 protein had no transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transactivation between KLF5 and NFKB1, another pivotal transcription factor that has been causally linked to DCM. The whole-exome sequencing analysis of the proband's family members revealed no other causative genes. The findings indicate KLF5 as a new gene contributing to DCM in humans, implying potential implications for the precision medicine of DCM.
- Subjects :
- 0301 basic medicine
Proband
Adult
Cardiomyopathy, Dilated
Male
Nonsense mutation
Kruppel-Like Transcription Factors
030105 genetics & heredity
Biology
medicine.disease_cause
03 medical and health sciences
Exon
Asian People
Chlorocebus aethiops
Genetics
medicine
Animals
Humans
Genetic Predisposition to Disease
cardiovascular diseases
Gene
Genetics (clinical)
Mutation
Genetic heterogeneity
General Medicine
Middle Aged
Penetrance
Transplantation
030104 developmental biology
COS Cells
cardiovascular system
Female
HeLa Cells
Subjects
Details
- ISSN :
- 18780849
- Volume :
- 63
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- European journal of medical genetics
- Accession number :
- edsair.doi.dedup.....fa6aa412b73410eaf11f2bf4b59eda8e