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Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome
Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a gen...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675478/ https://www.ncbi.nlm.nih.gov/pubmed/36134655 http://dx.doi.org/10.1172/jci.insight.156549 |
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author | Kitamura, Rie Asada Maxwell, Kristina G. Ye, Wenjuan Kries, Kelly Brown, Cris M. Augsornworawat, Punn Hirsch, Yoel Johansson, Martin M. Weiden, Tzvi Ekstein, Joseph Cohen, Joshua Klee, Justin Leslie, Kent Simeonov, Anton Henderson, Mark J. Millman, Jeffrey R. Urano, Fumihiko |
author_facet | Kitamura, Rie Asada Maxwell, Kristina G. Ye, Wenjuan Kries, Kelly Brown, Cris M. Augsornworawat, Punn Hirsch, Yoel Johansson, Martin M. Weiden, Tzvi Ekstein, Joseph Cohen, Joshua Klee, Justin Leslie, Kent Simeonov, Anton Henderson, Mark J. Millman, Jeffrey R. Urano, Fumihiko |
author_sort | Kitamura, Rie Asada |
collection | PubMed |
description | Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell–derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC–derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. |
format | Online Article Text |
id | pubmed-9675478 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-96754782022-11-21 Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome Kitamura, Rie Asada Maxwell, Kristina G. Ye, Wenjuan Kries, Kelly Brown, Cris M. Augsornworawat, Punn Hirsch, Yoel Johansson, Martin M. Weiden, Tzvi Ekstein, Joseph Cohen, Joshua Klee, Justin Leslie, Kent Simeonov, Anton Henderson, Mark J. Millman, Jeffrey R. Urano, Fumihiko JCI Insight Research Article Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell–derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC–derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. American Society for Clinical Investigation 2022-09-22 /pmc/articles/PMC9675478/ /pubmed/36134655 http://dx.doi.org/10.1172/jci.insight.156549 Text en © 2022 Kitamura et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Kitamura, Rie Asada Maxwell, Kristina G. Ye, Wenjuan Kries, Kelly Brown, Cris M. Augsornworawat, Punn Hirsch, Yoel Johansson, Martin M. Weiden, Tzvi Ekstein, Joseph Cohen, Joshua Klee, Justin Leslie, Kent Simeonov, Anton Henderson, Mark J. Millman, Jeffrey R. Urano, Fumihiko Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title | Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title_full | Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title_fullStr | Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title_full_unstemmed | Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title_short | Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome |
title_sort | multidimensional analysis and therapeutic development using patient ipsc–derived disease models of wolfram syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9675478/ https://www.ncbi.nlm.nih.gov/pubmed/36134655 http://dx.doi.org/10.1172/jci.insight.156549 |
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