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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-09-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.156549 |
| _version_ | 1797634345874227200 |
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| author | Rie Asada Kitamura Kristina G. Maxwell Wenjuan Ye Kelly Kries Cris M. Brown Punn Augsornworawat Yoel Hirsch Martin M. Johansson Tzvi Weiden Joseph Ekstein Joshua Cohen Justin Klee Kent Leslie Anton Simeonov Mark J. Henderson Jeffrey R. Millman Fumihiko Urano |
| author_facet | Rie Asada Kitamura Kristina G. Maxwell Wenjuan Ye Kelly Kries Cris M. Brown Punn Augsornworawat Yoel Hirsch Martin M. Johansson Tzvi Weiden Joseph Ekstein Joshua Cohen Justin Klee Kent Leslie Anton Simeonov Mark J. Henderson Jeffrey R. Millman Fumihiko Urano |
| author_sort | Rie Asada Kitamura |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:07:20Z |
| format | Article |
| id | doaj.art-24a5fd515d1d461683a1b821a7ee0008 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:07:20Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-24a5fd515d1d461683a1b821a7ee00082023-11-07T16:24:35ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-09-01718Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndromeRie Asada KitamuraKristina G. MaxwellWenjuan YeKelly KriesCris M. BrownPunn AugsornworawatYoel HirschMartin M. JohanssonTzvi WeidenJoseph EksteinJoshua CohenJustin KleeKent LeslieAnton SimeonovMark J. HendersonJeffrey R. MillmanFumihiko UranoWolfram 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.https://doi.org/10.1172/jci.insight.156549EndocrinologyGenetics |
| spellingShingle | Rie Asada Kitamura Kristina G. Maxwell Wenjuan Ye Kelly Kries Cris M. Brown Punn Augsornworawat Yoel Hirsch Martin M. Johansson Tzvi Weiden Joseph Ekstein Joshua Cohen Justin Klee Kent Leslie Anton Simeonov Mark J. Henderson Jeffrey R. Millman Fumihiko Urano Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome JCI Insight Endocrinology Genetics |
| 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 | Endocrinology Genetics |
| url | https://doi.org/10.1172/jci.insight.156549 |
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