Altered chaperone–nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome

• DOI: 10.1172/jci.insight.185508
• Publication Date: 2025-03-23T18:00:31Z
• Authors: Stephanie Waich; Karin Kreidl; Julia Vodopiutz; Arzu Meltem Demir; Adam R. Pollio; Vojtěch Dostál; Kristian Pfaller; Marianna Parlato; Nadine Cerf-Bensu...; Rüdiger Adam; Georg F. Vogel; Holm H. Uhlig; Frank M. Ruemmele; Thomas Müller; Michael W. Hess; Andreas R. Janecke; Lukas A. Huber; Taras Valovka
• Keywords: Chaperone (clinical)

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 (UNC45A) gene. clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular functional analysis of UNC45A c.710T>C (p.Leu237Pro) missense variant, which revealed unique pathogenicity compared other genetic variants causing deficiency. p.Leu237Pro mutant retained activity, prevented aggregation, supported proper nonmuscle II (NMII) filament formation patient fibroblasts human osteosarcoma (U2OS) cells. However, formed atypically stable oligomers chaperone-myosin complex dissociation, thereby inhibiting NMII functions. Similar biallelic deficiency, this resulted impaired intracellular trafficking, defective recycling, abnormal retention transferrin at various endocytic sites. In particular, coexpression wild-type protein attenuated pathogenic effects variant by excessive oligomer formation. Our results elucidate mechanisms characteristics may aid development targeted therapies.