Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia is a rare disease with autosomal dominant inheritance. More than 80% hereditary hemorrhagic telangiectasia patients carry heterozygous mutations of Endoglin or Activin receptor-like kinase-1 genes. Endoglin plays important roles in vasculogenesis and human vascu...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhou, Fang, Zhao, Xiuli, Liu, Xiu, Liu, Yanyan, Ma, Feng, Liu, Bao, Yang, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691931/
https://www.ncbi.nlm.nih.gov/pubmed/33282178
http://dx.doi.org/10.1177/2045894019885357
_version_ 1783614400022708224
author Zhou, Fang
Zhao, Xiuli
Liu, Xiu
Liu, Yanyan
Ma, Feng
Liu, Bao
Yang, Jun
author_facet Zhou, Fang
Zhao, Xiuli
Liu, Xiu
Liu, Yanyan
Ma, Feng
Liu, Bao
Yang, Jun
author_sort Zhou, Fang
collection PubMed
description Hereditary hemorrhagic telangiectasia is a rare disease with autosomal dominant inheritance. More than 80% hereditary hemorrhagic telangiectasia patients carry heterozygous mutations of Endoglin or Activin receptor-like kinase-1 genes. Endoglin plays important roles in vasculogenesis and human vascular disease. In this report, we found a novel missense mutation (c.88T > C) of Endoglin gene in a hereditary hemorrhagic telangiectasia 1 patient. Induced pluripotent stem cells of the patient were generated and differentiated into endothelial cells. The hereditary hemorrhagic telangiectasia-induced pluripotent stem cells have reduced differentiation potential toward vascular endothelial cells and defective angiogenesis with impaired tube formation. Endoplasmic reticulum retention of the mutant Endoglin (Cys30Arg, C30R) causes less functional protein trafficking to cell surface, which contributes to the pathogenesis of hereditary hemorrhagic telangiectasia. Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 genetic correction of the c.88T > C mutation in induced pluripotent stem cells revealed that C30R mutation of Endoglin affects bone morphogenetic protein 9 downstream signaling. By establishing a human induced pluripotent stem cell from hereditary hemorrhagic telangiectasia patient peripheral blood mononuclear cells and autologous correction on mutant hereditary hemorrhagic telangiectasia-induced pluripotent stem cells, we were able to identify a new disease-causing mutation, which facilitates us to understand the roles of Endoglin in vascular development and pathogenesis of related vascular diseases.
format Online
Article
Text
id pubmed-7691931
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher SAGE Publications
record_format MEDLINE/PubMed
spelling pubmed-76919312020-12-04 Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia Zhou, Fang Zhao, Xiuli Liu, Xiu Liu, Yanyan Ma, Feng Liu, Bao Yang, Jun Pulm Circ Original Research Article Hereditary hemorrhagic telangiectasia is a rare disease with autosomal dominant inheritance. More than 80% hereditary hemorrhagic telangiectasia patients carry heterozygous mutations of Endoglin or Activin receptor-like kinase-1 genes. Endoglin plays important roles in vasculogenesis and human vascular disease. In this report, we found a novel missense mutation (c.88T > C) of Endoglin gene in a hereditary hemorrhagic telangiectasia 1 patient. Induced pluripotent stem cells of the patient were generated and differentiated into endothelial cells. The hereditary hemorrhagic telangiectasia-induced pluripotent stem cells have reduced differentiation potential toward vascular endothelial cells and defective angiogenesis with impaired tube formation. Endoplasmic reticulum retention of the mutant Endoglin (Cys30Arg, C30R) causes less functional protein trafficking to cell surface, which contributes to the pathogenesis of hereditary hemorrhagic telangiectasia. Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 genetic correction of the c.88T > C mutation in induced pluripotent stem cells revealed that C30R mutation of Endoglin affects bone morphogenetic protein 9 downstream signaling. By establishing a human induced pluripotent stem cell from hereditary hemorrhagic telangiectasia patient peripheral blood mononuclear cells and autologous correction on mutant hereditary hemorrhagic telangiectasia-induced pluripotent stem cells, we were able to identify a new disease-causing mutation, which facilitates us to understand the roles of Endoglin in vascular development and pathogenesis of related vascular diseases. SAGE Publications 2020-11-25 /pmc/articles/PMC7691931/ /pubmed/33282178 http://dx.doi.org/10.1177/2045894019885357 Text en © The Author(s) 2020 https://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Original Research Article
Zhou, Fang
Zhao, Xiuli
Liu, Xiu
Liu, Yanyan
Ma, Feng
Liu, Bao
Yang, Jun
Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title_full Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title_fullStr Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title_full_unstemmed Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title_short Autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
title_sort autologous correction in patient induced pluripotent stem cell-endothelial cells to identify a novel pathogenic mutation of hereditary hemorrhagic telangiectasia
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691931/
https://www.ncbi.nlm.nih.gov/pubmed/33282178
http://dx.doi.org/10.1177/2045894019885357
work_keys_str_mv AT zhoufang autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT zhaoxiuli autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT liuxiu autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT liuyanyan autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT mafeng autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT liubao autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia
AT yangjun autologouscorrectioninpatientinducedpluripotentstemcellendothelialcellstoidentifyanovelpathogenicmutationofhereditaryhemorrhagictelangiectasia