{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T16:41:05Z","timestamp":1780764065597,"version":"3.54.1"},"reference-count":73,"publisher":"American Society for Clinical Investigation","issue":"6","license":[{"start":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T00:00:00Z","timestamp":1742774400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004061","name":"Oesterreichische Nationalbank","doi-asserted-by":"crossref","award":["Grant Number 17627"],"award-info":[{"award-number":["Grant Number 17627"]}],"id":[{"id":"10.13039\/501100004061","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,24]]},"abstract":"<jats:p>\n                    The osteo-oto-hepato-enteric (O2HE) syndrome is a severe autosomal recessive disease ascribed to loss-of-function mutations in the Unc-45 myosin chaperone A (\n                    <jats:italic>UNC45A<\/jats:italic>\n                    ) gene. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease\u2013like enteropathy. Here, we present molecular and functional analysis of the\n                    <jats:italic>UNC45A<\/jats:italic>\n                    c.710T&gt;C (p.Leu237Pro) missense variant, which revealed a unique pathogenicity compared with other genetic variants causing UNC45A deficiency. The UNC45A p.Leu237Pro mutant retained chaperone activity, prevented myosin aggregation, and supported proper nonmuscle myosin II (NMII) filament formation in patient fibroblasts and human osteosarcoma (U2OS) cells. However, the mutant formed atypically stable oligomers and prevented chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar to biallelic UNC45A deficiency, this resulted in impaired intracellular trafficking, defective recycling, and abnormal retention of transferrin at various endocytic sites. In particular, coexpression of wild-type protein attenuated the pathogenic effects of the variant by inhibiting excessive oligomer formation. Our results elucidate the pathogenic mechanisms and recessive characteristics of this variant and may aid in the development of targeted therapies.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.185508","type":"journal-article","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T14:00:31Z","timestamp":1742738431000},"source":"Crossref","is-referenced-by-count":1,"title":["Altered chaperone\u2013nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T&gt;C variant in osteo-oto-hepato-enteric syndrome"],"prefix":"10.1172","volume":"10","author":[{"given":"Stephanie","family":"Waich","sequence":"first","affiliation":[{"name":"Institute of Cell Biology, Biocenter, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Kreidl","sequence":"additional","affiliation":[{"name":"Institute of Cell Biology, Biocenter, and"},{"name":"Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, 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