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Mutations in EPAS1 in congenital heart disease in Tibetans

EPAS1 encodes HIF2 and is closely related to high altitude chronic hypoxia. Mutations in the EPAS1 coding sequence are associated with several kinds of human diseases, including syndromic congenital heart disease (CHD). However, whether there are rare EPAS1 coding variants related to Tibetan non-syn...

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Autores principales: Pan, Hong, Chen, Qiuhong, Qi, Shenggui, Li, Tengyan, Liu, Beihong, Liu, Shiming, Ma, Xu, Wang, Binbin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435565/
https://www.ncbi.nlm.nih.gov/pubmed/30487161
http://dx.doi.org/10.1042/BSR20181389
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author Pan, Hong
Chen, Qiuhong
Qi, Shenggui
Li, Tengyan
Liu, Beihong
Liu, Shiming
Ma, Xu
Wang, Binbin
author_facet Pan, Hong
Chen, Qiuhong
Qi, Shenggui
Li, Tengyan
Liu, Beihong
Liu, Shiming
Ma, Xu
Wang, Binbin
author_sort Pan, Hong
collection PubMed
description EPAS1 encodes HIF2 and is closely related to high altitude chronic hypoxia. Mutations in the EPAS1 coding sequence are associated with several kinds of human diseases, including syndromic congenital heart disease (CHD). However, whether there are rare EPAS1 coding variants related to Tibetan non-syndromic CHD have not been fully investigated. A group of 286 Tibetan patients with non-syndromic CHD and 250 unrelated Tibetan healthy controls were recruited from Qinghai, China. Sanger sequencing was performed to identify variations in the EPAS1 coding sequence. The novelty of identified variants was confirmed by the examination of 1000G and ExAC databases. Control samples were screened to establish that the rare candidate variants were specific to the Tibetan patients with non-syndromic CHD. Bioinformatics software was used to assess the conservation of the mutations and to predict their effects. The effect of EPAS1 mutations on the transcription of its target gene, VEGF, was assessed by dual-luciferase reporter assay. The mammalian two-hybrid assay was used to study the protein interactions between HIF2 and PHD2 or pVHL. We identified two novel EPAS1 mutations (NM_001430: c.607A>C, p.N203H; c.2170G>T, p.G724W) in two patients. The N203H mutation significantly affected the transcription activity of the VEGF promoter, especially in conditions of hypoxia. The N203H mutation also showed enhanced protein–protein interactions between HIF2 and PHD2, and HIF2 and pVHL, especially in conditions of hypoxia. However, the G724W mutation did not demonstrate the same effects. Our results indicate that EPAS1 mutations might have a potential causative effect on the development of Tibetan non-syndromic CHD.
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spelling pubmed-64355652019-04-12 Mutations in EPAS1 in congenital heart disease in Tibetans Pan, Hong Chen, Qiuhong Qi, Shenggui Li, Tengyan Liu, Beihong Liu, Shiming Ma, Xu Wang, Binbin Biosci Rep Research Articles EPAS1 encodes HIF2 and is closely related to high altitude chronic hypoxia. Mutations in the EPAS1 coding sequence are associated with several kinds of human diseases, including syndromic congenital heart disease (CHD). However, whether there are rare EPAS1 coding variants related to Tibetan non-syndromic CHD have not been fully investigated. A group of 286 Tibetan patients with non-syndromic CHD and 250 unrelated Tibetan healthy controls were recruited from Qinghai, China. Sanger sequencing was performed to identify variations in the EPAS1 coding sequence. The novelty of identified variants was confirmed by the examination of 1000G and ExAC databases. Control samples were screened to establish that the rare candidate variants were specific to the Tibetan patients with non-syndromic CHD. Bioinformatics software was used to assess the conservation of the mutations and to predict their effects. The effect of EPAS1 mutations on the transcription of its target gene, VEGF, was assessed by dual-luciferase reporter assay. The mammalian two-hybrid assay was used to study the protein interactions between HIF2 and PHD2 or pVHL. We identified two novel EPAS1 mutations (NM_001430: c.607A>C, p.N203H; c.2170G>T, p.G724W) in two patients. The N203H mutation significantly affected the transcription activity of the VEGF promoter, especially in conditions of hypoxia. The N203H mutation also showed enhanced protein–protein interactions between HIF2 and PHD2, and HIF2 and pVHL, especially in conditions of hypoxia. However, the G724W mutation did not demonstrate the same effects. Our results indicate that EPAS1 mutations might have a potential causative effect on the development of Tibetan non-syndromic CHD. Portland Press Ltd. 2018-12-18 /pmc/articles/PMC6435565/ /pubmed/30487161 http://dx.doi.org/10.1042/BSR20181389 Text en © 2018 The Author(s). http://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (http://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Pan, Hong
Chen, Qiuhong
Qi, Shenggui
Li, Tengyan
Liu, Beihong
Liu, Shiming
Ma, Xu
Wang, Binbin
Mutations in EPAS1 in congenital heart disease in Tibetans
title Mutations in EPAS1 in congenital heart disease in Tibetans
title_full Mutations in EPAS1 in congenital heart disease in Tibetans
title_fullStr Mutations in EPAS1 in congenital heart disease in Tibetans
title_full_unstemmed Mutations in EPAS1 in congenital heart disease in Tibetans
title_short Mutations in EPAS1 in congenital heart disease in Tibetans
title_sort mutations in epas1 in congenital heart disease in tibetans
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435565/
https://www.ncbi.nlm.nih.gov/pubmed/30487161
http://dx.doi.org/10.1042/BSR20181389
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