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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...
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Published in: | Experimental and therapeutic medicine 2018-01, Vol.15 (1), p.447-453 |
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container_title | Experimental and therapeutic medicine |
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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 |
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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> |
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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 |
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