Altered chaperone–nonmuscle myosin II interactions drive pathogenicity of the UNC45A c.710T>C variant in osteo-oto-hepato-enteric syndrome
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. The clinical spectrum includes bone fragility, hearing loss, cholestasis, and life-threatening diarrhea associated with microvillus inclusion disease-like enteropathy. Here, we present molecular and functional analysis of the UNC45A c.710T>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.
Authors
- Marianna Parlato (ORCID: https://orcid.org/0000-0002-8750-082X)
- Nadine Cerf–Bensussan (ORCID: https://orcid.org/0000-0003-0665-1245)
- Arzu Meltem Demir (ORCID: https://orcid.org/0000-0002-9176-9100)
- Rüdiger Adam (ORCID: https://orcid.org/0000-0003-2150-8199)
- Lukas Alfons Huber (ORCID: https://orcid.org/0000-0003-1116-2120)
- Frank M. Ruemmele (ORCID: https://orcid.org/0000-0001-5571-4957)
- Georg Friedrich Vogel (ORCID: https://orcid.org/0000-0002-2515-4490)
- Karin Kreidl
- Julia Vodopiutz (ORCID: https://orcid.org/0000-0002-8087-7026)
- Andreas Janecke (ORCID: https://orcid.org/0000-0001-7155-0315)
- Holm H. Uhlig (ORCID: https://orcid.org/0000-0002-6111-7355)
- Vojtěch Dostál (ORCID: https://orcid.org/0000-0002-8132-5856)
- Stephanie Waich
- Taras Valovka (ORCID: https://orcid.org/0000-0002-1205-2225)
- Thomas Müller (ORCID: https://orcid.org/0000-0001-8908-5589)
- Michael W. Hess (ORCID: https://orcid.org/0000-0002-5154-3553)
- Kristian Pfaller
- Adam R. Pollio
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Ministry of Health (TR)
- Innsbruck Medical University (AT)
- Ankara University (TR)
- Inserm (FR)
- University of Mannheim (DE)
- Universität Innsbruck (AT)
- Université Paris Cité (FR)
- Heidelberg University (DE)
- Nuffield Orthopaedic Centre (GB)
- University Hospital Heidelberg (DE)
- University of Oxford (GB)
- Institut Necker Enfants Malades (FR)
- Comprehensive Cancer Center Vienna (AT)
- Assistance Publique – Hôpitaux de Paris (FR)
- Vienna Biocenter (AT)
- Oxford BioMedica (United Kingdom) (GB)
- University Medical Centre Mannheim (DE)
- Institut des Maladies Génétiques Imagine (FR)
- Medical University of Vienna (AT)
Publication Details
- Journal
- JCI Insight
- Published
- 2025-03-23
- DOI
- https://doi.org/10.1172/jci.insight.185508
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Oesterreichische Nationalbank