{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:08Z","timestamp":1787018348394,"version":"build-2736575974"},"reference-count":84,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK112921,DK020579,TR002065,TR000448,TR002345"],"award-info":[{"award-number":["DK112921,DK020579,TR002065,TR000448,TR002345"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK132090"],"award-info":[{"award-number":["DK132090"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,22]]},"abstract":"<jats:p>\n                    Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the\n                    <jats:italic>WFS1<\/jats:italic>\n                    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\n                    <jats:italic>WFS1<\/jats:italic>\n                    c.1672C&gt;T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous\n                    <jats:italic>WFS1<\/jats:italic>\n                    c.1672C&gt;T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of\n                    <jats:italic>WFS1<\/jats:italic>\n                    p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell\u2013derived (iPSC-derived) islets (SC-islets) homozygous for\n                    <jats:italic>WFS1<\/jats:italic>\n                    c.1672C&gt;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\n                    <jats:italic>WFS1<\/jats:italic>\n                    c.1672C&gt;T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the\n                    <jats:italic>WFS1<\/jats:italic>\n                    c.1672C&gt;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\u2013derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.156549","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T14:00:48Z","timestamp":1663768848000},"source":"Crossref","is-referenced-by-count":36,"title":["Multidimensional analysis and therapeutic development using patient iPSC\u2013derived disease models of Wolfram syndrome"],"prefix":"10.1172","volume":"7","author":[{"given":"Rie Asada","family":"Kitamura","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-1662","authenticated-orcid":true,"given":"Kristina 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cris M.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-5433","authenticated-orcid":true,"given":"Punn","family":"Augsornworawat","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA."},{"name":"Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, 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USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Cohen","sequence":"additional","affiliation":[{"name":"Amylyx Pharmaceuticals Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Klee","sequence":"additional","affiliation":[{"name":"Amylyx Pharmaceuticals Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent","family":"Leslie","sequence":"additional","affiliation":[{"name":"Amylyx Pharmaceuticals Inc., Cambridge, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4523-9977","authenticated-orcid":true,"given":"Anton","family":"Simeonov","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, Maryland, 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