TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway.
<h4>Background</h4>TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also b...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0227393 |
| _version_ | 1819128768403341312 |
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| author | Nariaki Miyao Yukiko Hata Hironori Izumi Ryo Nagaoka Yuko Oku Ichiro Takasaki Taisuke Ishikawa Shinya Takarada Mako Okabe Hideyuki Nakaoka Keijiro Ibuki Sayaka Ozawa Tomoyuki Yoshida Hideyuki Hasegawa Naomasa Makita Naoki Nishida Hisashi Mori Fukiko Ichida Keiichi Hirono |
| author_facet | Nariaki Miyao Yukiko Hata Hironori Izumi Ryo Nagaoka Yuko Oku Ichiro Takasaki Taisuke Ishikawa Shinya Takarada Mako Okabe Hideyuki Nakaoka Keijiro Ibuki Sayaka Ozawa Tomoyuki Yoshida Hideyuki Hasegawa Naomasa Makita Naoki Nishida Hisashi Mori Fukiko Ichida Keiichi Hirono |
| author_sort | Nariaki Miyao |
| collection | DOAJ |
| description | <h4>Background</h4>TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses.<h4>Objective</h4>To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy.<h4>Methods and results</h4>We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1.<h4>Conclusions</h4>Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway. |
| first_indexed | 2024-12-22T08:33:04Z |
| format | Article |
| id | doaj.art-809709f73e3443efbc25317e9318720c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T08:33:04Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-809709f73e3443efbc25317e9318720c2022-12-21T18:32:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01154e022739310.1371/journal.pone.0227393TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway.Nariaki MiyaoYukiko HataHironori IzumiRyo NagaokaYuko OkuIchiro TakasakiTaisuke IshikawaShinya TakaradaMako OkabeHideyuki NakaokaKeijiro IbukiSayaka OzawaTomoyuki YoshidaHideyuki HasegawaNaomasa MakitaNaoki NishidaHisashi MoriFukiko IchidaKeiichi Hirono<h4>Background</h4>TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses.<h4>Objective</h4>To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy.<h4>Methods and results</h4>We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1.<h4>Conclusions</h4>Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway.https://doi.org/10.1371/journal.pone.0227393 |
| spellingShingle | Nariaki Miyao Yukiko Hata Hironori Izumi Ryo Nagaoka Yuko Oku Ichiro Takasaki Taisuke Ishikawa Shinya Takarada Mako Okabe Hideyuki Nakaoka Keijiro Ibuki Sayaka Ozawa Tomoyuki Yoshida Hideyuki Hasegawa Naomasa Makita Naoki Nishida Hisashi Mori Fukiko Ichida Keiichi Hirono TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. PLoS ONE |
| title | TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. |
| title_full | TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. |
| title_fullStr | TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. |
| title_full_unstemmed | TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. |
| title_short | TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway. |
| title_sort | tbx5 r264k acts as a modifier to develop dilated cardiomyopathy in mice independently of t box pathway |
| url | https://doi.org/10.1371/journal.pone.0227393 |
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