Loading…

TBX1 loss-of-function mutation contributes to congenital conotruncal defects

Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the gene that cod...

Full description

Saved in:
Bibliographic Details
Published in:Experimental and therapeutic medicine 2018-01, Vol.15 (1), p.447-453
Main Authors: Zhang, Min, Li, Fu-Xing, Liu, Xing-Yuan, Hou, Jing-Yi, Ni, Shi-Hong, Wang, Juan, Zhao, Cui-Mei, Zhang, Wei, Kong, Ye, Huang, Ri-Tai, Xue, Song, Yang, Yi-Qing
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3
cites cdi_FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3
container_end_page 453
container_issue 1
container_start_page 447
container_title Experimental and therapeutic medicine
container_volume 15
creator Zhang, Min
Li, Fu-Xing
Liu, Xing-Yuan
Hou, Jing-Yi
Ni, Shi-Hong
Wang, Juan
Zhao, Cui-Mei
Zhang, Wei
Kong, Ye
Huang, Ri-Tai
Xue, Song
Yang, Yi-Qing
description Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic . Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.
doi_str_mv 10.3892/etm.2017.5362
format article
fullrecord <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5729719</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A528467460</galeid><sourcerecordid>A528467460</sourcerecordid><originalsourceid>FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3</originalsourceid><addsrcrecordid>eNptkU1LAzEQhoMoVrRHr1Lw4mXrJrvJJhdBxS8oeKngLSTppEZ2N3WTFfz3Zm0tFkwOeZM8M8zMi9ApzqcFF-QSYjMlOa6mtGBkDx3hSpAM55jub3QuOB6hcQjveVqUYc7pIRoRQWiixBGazW9e8aT2IWTeZrZvTXS-nTR9VD_C-DZ2TvcRwiT64bqE1kVVD9LHLgUkvQALJoYTdGBVHWC8OY_Ry_3d_PYxmz0_PN1ezzJT0jJmGIAREEQTojmxRlGbmqkUpapklOlcaYbLVCEpKzCkZFxpy1lhFCbaalUco6t13lWvG1gYSDWqWq4616juS3rl5O5P697k0n9KWhFRYZESXGwSdP6jhxBl44KBulYt-D5ILCpeYIrFgJ6v0aWqQbrWpqaVGXB5TQkvWVWyPFHTf6i0F9C4NCmwLr3vBGTrANOl2Xdgt9XjXA7eyuStHLyVg7eJP_vb8pb-dbL4Bryqn8U</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1978315199</pqid></control><display><type>article</type><title>TBX1 loss-of-function mutation contributes to congenital conotruncal defects</title><source>Open Access: PubMed Central</source><creator>Zhang, Min ; Li, Fu-Xing ; Liu, Xing-Yuan ; Hou, Jing-Yi ; Ni, Shi-Hong ; Wang, Juan ; Zhao, Cui-Mei ; Zhang, Wei ; Kong, Ye ; Huang, Ri-Tai ; Xue, Song ; Yang, Yi-Qing</creator><creatorcontrib>Zhang, Min ; Li, Fu-Xing ; Liu, Xing-Yuan ; Hou, Jing-Yi ; Ni, Shi-Hong ; Wang, Juan ; Zhao, Cui-Mei ; Zhang, Wei ; Kong, Ye ; Huang, Ri-Tai ; Xue, Song ; Yang, Yi-Qing</creatorcontrib><description>Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic . Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.</description><identifier>ISSN: 1792-0981</identifier><identifier>EISSN: 1792-1015</identifier><identifier>DOI: 10.3892/etm.2017.5362</identifier><identifier>PMID: 29250159</identifier><language>eng</language><publisher>Greece: Spandidos Publications</publisher><subject>Analysis ; China ; Congenital heart defects ; Gene mutation ; Genetic aspects ; Medical research ; Mortality ; Physiological aspects ; Transcription factors</subject><ispartof>Experimental and therapeutic medicine, 2018-01, Vol.15 (1), p.447-453</ispartof><rights>COPYRIGHT 2018 Spandidos Publications</rights><rights>Copyright © 2018, Spandidos Publications 2018</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3</citedby><cites>FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729719/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729719/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29250159$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Min</creatorcontrib><creatorcontrib>Li, Fu-Xing</creatorcontrib><creatorcontrib>Liu, Xing-Yuan</creatorcontrib><creatorcontrib>Hou, Jing-Yi</creatorcontrib><creatorcontrib>Ni, Shi-Hong</creatorcontrib><creatorcontrib>Wang, Juan</creatorcontrib><creatorcontrib>Zhao, Cui-Mei</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Kong, Ye</creatorcontrib><creatorcontrib>Huang, Ri-Tai</creatorcontrib><creatorcontrib>Xue, Song</creatorcontrib><creatorcontrib>Yang, Yi-Qing</creatorcontrib><title>TBX1 loss-of-function mutation contributes to congenital conotruncal defects</title><title>Experimental and therapeutic medicine</title><addtitle>Exp Ther Med</addtitle><description>Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic . Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.</description><subject>Analysis</subject><subject>China</subject><subject>Congenital heart defects</subject><subject>Gene mutation</subject><subject>Genetic aspects</subject><subject>Medical research</subject><subject>Mortality</subject><subject>Physiological aspects</subject><subject>Transcription factors</subject><issn>1792-0981</issn><issn>1792-1015</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNptkU1LAzEQhoMoVrRHr1Lw4mXrJrvJJhdBxS8oeKngLSTppEZ2N3WTFfz3Zm0tFkwOeZM8M8zMi9ApzqcFF-QSYjMlOa6mtGBkDx3hSpAM55jub3QuOB6hcQjveVqUYc7pIRoRQWiixBGazW9e8aT2IWTeZrZvTXS-nTR9VD_C-DZ2TvcRwiT64bqE1kVVD9LHLgUkvQALJoYTdGBVHWC8OY_Ry_3d_PYxmz0_PN1ezzJT0jJmGIAREEQTojmxRlGbmqkUpapklOlcaYbLVCEpKzCkZFxpy1lhFCbaalUco6t13lWvG1gYSDWqWq4616juS3rl5O5P697k0n9KWhFRYZESXGwSdP6jhxBl44KBulYt-D5ILCpeYIrFgJ6v0aWqQbrWpqaVGXB5TQkvWVWyPFHTf6i0F9C4NCmwLr3vBGTrANOl2Xdgt9XjXA7eyuStHLyVg7eJP_vb8pb-dbL4Bryqn8U</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Zhang, Min</creator><creator>Li, Fu-Xing</creator><creator>Liu, Xing-Yuan</creator><creator>Hou, Jing-Yi</creator><creator>Ni, Shi-Hong</creator><creator>Wang, Juan</creator><creator>Zhao, Cui-Mei</creator><creator>Zhang, Wei</creator><creator>Kong, Ye</creator><creator>Huang, Ri-Tai</creator><creator>Xue, Song</creator><creator>Yang, Yi-Qing</creator><general>Spandidos Publications</general><general>D.A. Spandidos</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180101</creationdate><title>TBX1 loss-of-function mutation contributes to congenital conotruncal defects</title><author>Zhang, Min ; Li, Fu-Xing ; Liu, Xing-Yuan ; Hou, Jing-Yi ; Ni, Shi-Hong ; Wang, Juan ; Zhao, Cui-Mei ; Zhang, Wei ; Kong, Ye ; Huang, Ri-Tai ; Xue, Song ; Yang, Yi-Qing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Analysis</topic><topic>China</topic><topic>Congenital heart defects</topic><topic>Gene mutation</topic><topic>Genetic aspects</topic><topic>Medical research</topic><topic>Mortality</topic><topic>Physiological aspects</topic><topic>Transcription factors</topic><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Min</creatorcontrib><creatorcontrib>Li, Fu-Xing</creatorcontrib><creatorcontrib>Liu, Xing-Yuan</creatorcontrib><creatorcontrib>Hou, Jing-Yi</creatorcontrib><creatorcontrib>Ni, Shi-Hong</creatorcontrib><creatorcontrib>Wang, Juan</creatorcontrib><creatorcontrib>Zhao, Cui-Mei</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Kong, Ye</creatorcontrib><creatorcontrib>Huang, Ri-Tai</creatorcontrib><creatorcontrib>Xue, Song</creatorcontrib><creatorcontrib>Yang, Yi-Qing</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Experimental and therapeutic medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Min</au><au>Li, Fu-Xing</au><au>Liu, Xing-Yuan</au><au>Hou, Jing-Yi</au><au>Ni, Shi-Hong</au><au>Wang, Juan</au><au>Zhao, Cui-Mei</au><au>Zhang, Wei</au><au>Kong, Ye</au><au>Huang, Ri-Tai</au><au>Xue, Song</au><au>Yang, Yi-Qing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TBX1 loss-of-function mutation contributes to congenital conotruncal defects</atitle><jtitle>Experimental and therapeutic medicine</jtitle><addtitle>Exp Ther Med</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>15</volume><issue>1</issue><spage>447</spage><epage>453</epage><pages>447-453</pages><issn>1792-0981</issn><eissn>1792-1015</eissn><abstract>Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the gene that codes for a T-box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic . Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA.</abstract><cop>Greece</cop><pub>Spandidos Publications</pub><pmid>29250159</pmid><doi>10.3892/etm.2017.5362</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1792-0981
ispartof Experimental and therapeutic medicine, 2018-01, Vol.15 (1), p.447-453
issn 1792-0981
1792-1015
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5729719
source Open Access: PubMed Central
subjects Analysis
China
Congenital heart defects
Gene mutation
Genetic aspects
Medical research
Mortality
Physiological aspects
Transcription factors
title TBX1 loss-of-function mutation contributes to congenital conotruncal defects
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-04T19%3A45%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TBX1%20loss-of-function%20mutation%20contributes%20to%20congenital%20conotruncal%20defects&rft.jtitle=Experimental%20and%20therapeutic%20medicine&rft.au=Zhang,%20Min&rft.date=2018-01-01&rft.volume=15&rft.issue=1&rft.spage=447&rft.epage=453&rft.pages=447-453&rft.issn=1792-0981&rft.eissn=1792-1015&rft_id=info:doi/10.3892/etm.2017.5362&rft_dat=%3Cgale_pubme%3EA528467460%3C/gale_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c454t-1ee62e92b22b82fca5f8927a55a4656b0ab614250247ec2468abf863ca12bfba3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1978315199&rft_id=info:pmid/29250159&rft_galeid=A528467460&rfr_iscdi=true