Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy
Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and sp...
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Veröffentlicht in: | International Heart Journal 2017, Vol.58(4), pp.521-529 |
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creator | Xu, Jia-Hong Gu, Jian-Yun Guo, Yu-Han Zhang, Hong Qiu, Xing-Biao Li, Ruo-Gu Shi, Hong-Yu Liu, Hua Yang, Xiao-Xiao Xu, Ying-Jia Qu, Xin-Kai Yang, Yi-Qing |
description | Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients. |
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Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.</description><identifier>ISSN: 1349-2365</identifier><identifier>EISSN: 1349-3299</identifier><identifier>DOI: 10.1536/ihj.16-440</identifier><identifier>PMID: 28690296</identifier><language>eng</language><publisher>Japan: International Heart Journal Association</publisher><subject>Age of Onset ; Cardiomyopathy ; Cardiomyopathy, Dilated - epidemiology ; Cardiomyopathy, Dilated - genetics ; Cardiomyopathy, Dilated - metabolism ; China - epidemiology ; Chromosomes ; Congestive heart failure ; Dilated cardiomyopathy ; DNA - genetics ; DNA Mutational Analysis ; Etiology ; Female ; Follow-Up Studies ; Genes, Reporter - genetics ; Genetic counseling ; Genetics ; Genotype ; Heart failure ; Heart transplantation ; Homeobox Protein Nkx-2.5 - genetics ; Homeobox Protein Nkx-2.5 - metabolism ; Humans ; Introns ; Male ; Middle Aged ; Mutation ; Nkx2.5 protein ; Patients ; Pedigree ; Polymerase Chain Reaction ; Prevalence ; Reporter gene assay ; Transcription factors ; Transcriptional factor</subject><ispartof>International Heart Journal, 2017, Vol.58(4), pp.521-529</ispartof><rights>2017 by the International Heart Journal Association</rights><rights>Copyright Japan Science and Technology Agency 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c498t-2332513d096854a3aac44d7fd392c81fca902106ab2a3698784a5b47ed044ae33</citedby><cites>FETCH-LOGICAL-c498t-2332513d096854a3aac44d7fd392c81fca902106ab2a3698784a5b47ed044ae33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28690296$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Jia-Hong</creatorcontrib><creatorcontrib>Gu, Jian-Yun</creatorcontrib><creatorcontrib>Guo, Yu-Han</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Qiu, Xing-Biao</creatorcontrib><creatorcontrib>Li, Ruo-Gu</creatorcontrib><creatorcontrib>Shi, Hong-Yu</creatorcontrib><creatorcontrib>Liu, Hua</creatorcontrib><creatorcontrib>Yang, Xiao-Xiao</creatorcontrib><creatorcontrib>Xu, Ying-Jia</creatorcontrib><creatorcontrib>Qu, Xin-Kai</creatorcontrib><creatorcontrib>Yang, Yi-Qing</creatorcontrib><title>Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy</title><title>International Heart Journal</title><addtitle>Int. Heart J.</addtitle><description>Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.</description><subject>Age of Onset</subject><subject>Cardiomyopathy</subject><subject>Cardiomyopathy, Dilated - epidemiology</subject><subject>Cardiomyopathy, Dilated - genetics</subject><subject>Cardiomyopathy, Dilated - metabolism</subject><subject>China - epidemiology</subject><subject>Chromosomes</subject><subject>Congestive heart failure</subject><subject>Dilated cardiomyopathy</subject><subject>DNA - genetics</subject><subject>DNA Mutational Analysis</subject><subject>Etiology</subject><subject>Female</subject><subject>Follow-Up Studies</subject><subject>Genes, Reporter - genetics</subject><subject>Genetic counseling</subject><subject>Genetics</subject><subject>Genotype</subject><subject>Heart failure</subject><subject>Heart transplantation</subject><subject>Homeobox Protein Nkx-2.5 - genetics</subject><subject>Homeobox Protein Nkx-2.5 - metabolism</subject><subject>Humans</subject><subject>Introns</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Nkx2.5 protein</subject><subject>Patients</subject><subject>Pedigree</subject><subject>Polymerase Chain Reaction</subject><subject>Prevalence</subject><subject>Reporter gene assay</subject><subject>Transcription factors</subject><subject>Transcriptional factor</subject><issn>1349-2365</issn><issn>1349-3299</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo90MtqGzEUBmARGpo06aYPUATdFSbR3aNdjXtJyK3QlnQnjiVNLDMeuZKm4LePHDveSAJ9_Dr6EfpAyQWVXF2GxfKCqkYIcoROKRe64UzrN_sz40qeoHc5LwkRVJLJW3TCWqUJ0-oUPf1M_j_0frAew-Dwr7W3JY0rHDt8f_OXNRLfjQVKiEPG05yjDVC8w4-hLCqOCVyweOrGvjQPQ_YFfw39i5hBciGuNnENZbE5R8cd9Nm_3-9n6M_3b79nV83tw4_r2fS2sUK3pQ7LmaTcEa1aKYADWCHcpHNcM9vSzkKdmxIFcwZc6XbSCpBzMfGOCAGe8zP0aZe7TvHf6HMxyzimoT5pGKm_51Korfq8UzbFnJPvzDqFFaSNocRsOzW1U0OVqZ1W_HEfOc5X3h3oa4kVfNmBZS7w5A8AUgm29y9ZsjViu-wyD1d2Acn4gT8DU3CIPA</recordid><startdate>20170101</startdate><enddate>20170101</enddate><creator>Xu, Jia-Hong</creator><creator>Gu, Jian-Yun</creator><creator>Guo, Yu-Han</creator><creator>Zhang, Hong</creator><creator>Qiu, Xing-Biao</creator><creator>Li, Ruo-Gu</creator><creator>Shi, Hong-Yu</creator><creator>Liu, Hua</creator><creator>Yang, Xiao-Xiao</creator><creator>Xu, Ying-Jia</creator><creator>Qu, Xin-Kai</creator><creator>Yang, Yi-Qing</creator><general>International Heart Journal Association</general><general>Japan Science and Technology Agency</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope></search><sort><creationdate>20170101</creationdate><title>Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy</title><author>Xu, Jia-Hong ; Gu, Jian-Yun ; Guo, Yu-Han ; Zhang, Hong ; Qiu, Xing-Biao ; Li, Ruo-Gu ; Shi, Hong-Yu ; Liu, Hua ; Yang, Xiao-Xiao ; Xu, Ying-Jia ; Qu, Xin-Kai ; Yang, Yi-Qing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c498t-2332513d096854a3aac44d7fd392c81fca902106ab2a3698784a5b47ed044ae33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Age of Onset</topic><topic>Cardiomyopathy</topic><topic>Cardiomyopathy, Dilated - epidemiology</topic><topic>Cardiomyopathy, Dilated - genetics</topic><topic>Cardiomyopathy, Dilated - metabolism</topic><topic>China - epidemiology</topic><topic>Chromosomes</topic><topic>Congestive heart failure</topic><topic>Dilated cardiomyopathy</topic><topic>DNA - genetics</topic><topic>DNA Mutational Analysis</topic><topic>Etiology</topic><topic>Female</topic><topic>Follow-Up Studies</topic><topic>Genes, Reporter - genetics</topic><topic>Genetic counseling</topic><topic>Genetics</topic><topic>Genotype</topic><topic>Heart failure</topic><topic>Heart transplantation</topic><topic>Homeobox Protein Nkx-2.5 - genetics</topic><topic>Homeobox Protein Nkx-2.5 - metabolism</topic><topic>Humans</topic><topic>Introns</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Nkx2.5 protein</topic><topic>Patients</topic><topic>Pedigree</topic><topic>Polymerase Chain Reaction</topic><topic>Prevalence</topic><topic>Reporter gene assay</topic><topic>Transcription factors</topic><topic>Transcriptional factor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Jia-Hong</creatorcontrib><creatorcontrib>Gu, Jian-Yun</creatorcontrib><creatorcontrib>Guo, Yu-Han</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Qiu, Xing-Biao</creatorcontrib><creatorcontrib>Li, Ruo-Gu</creatorcontrib><creatorcontrib>Shi, Hong-Yu</creatorcontrib><creatorcontrib>Liu, Hua</creatorcontrib><creatorcontrib>Yang, Xiao-Xiao</creatorcontrib><creatorcontrib>Xu, Ying-Jia</creatorcontrib><creatorcontrib>Qu, Xin-Kai</creatorcontrib><creatorcontrib>Yang, Yi-Qing</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><jtitle>International Heart Journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Jia-Hong</au><au>Gu, Jian-Yun</au><au>Guo, Yu-Han</au><au>Zhang, Hong</au><au>Qiu, Xing-Biao</au><au>Li, Ruo-Gu</au><au>Shi, Hong-Yu</au><au>Liu, Hua</au><au>Yang, Xiao-Xiao</au><au>Xu, Ying-Jia</au><au>Qu, Xin-Kai</au><au>Yang, Yi-Qing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy</atitle><jtitle>International Heart Journal</jtitle><addtitle>Int. Heart J.</addtitle><date>2017-01-01</date><risdate>2017</risdate><volume>58</volume><issue>4</issue><spage>521</spage><epage>529</epage><pages>521-529</pages><issn>1349-2365</issn><eissn>1349-3299</eissn><abstract>Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.</abstract><cop>Japan</cop><pub>International Heart Journal Association</pub><pmid>28690296</pmid><doi>10.1536/ihj.16-440</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Age of Onset Cardiomyopathy Cardiomyopathy, Dilated - epidemiology Cardiomyopathy, Dilated - genetics Cardiomyopathy, Dilated - metabolism China - epidemiology Chromosomes Congestive heart failure Dilated cardiomyopathy DNA - genetics DNA Mutational Analysis Etiology Female Follow-Up Studies Genes, Reporter - genetics Genetic counseling Genetics Genotype Heart failure Heart transplantation Homeobox Protein Nkx-2.5 - genetics Homeobox Protein Nkx-2.5 - metabolism Humans Introns Male Middle Aged Mutation Nkx2.5 protein Patients Pedigree Polymerase Chain Reaction Prevalence Reporter gene assay Transcription factors Transcriptional factor |
title | Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy |
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