UNC45A deficiency causes microvillus inclusion disease-like phenotype by impairing myosin VB-dependent apical trafficking.

Autor: Duclaux-Loras R; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France.; Department of Pediatric Gastroenterology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, F-75015, Paris, France., Lebreton C; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France., Berthelet J; Université Paris Cité, CEDC, UMR 7216, CNRS, Paris, France., Charbit-Henrion F; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France.; Department of Pediatric Gastroenterology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, F-75015, Paris, France., Nicolle O; Université de Rennes, CNRS, Institut de Génétique et Développement de Rennes (IGDR)-UMR 6290, Rennes, France., Revenu des Courtils C; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, Paris, France., Waich S; Universitätsklinik für Pädiatrie I and.; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Valovka T; Universitätsklinik für Pädiatrie I and.; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Khiat A; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France., Rabant M; Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, Paris, France., Racine C; Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire, and Equipe GAD, Université de Bourgogne Franche-Comté, Faculté de Médecine, INSERM LNC UMR 1231, Dijon, France., Guerrera IC; Proteomics Platform 3P5-Necker, Université Paris Descartes-Structure Fédérative de Recherche Necker, INSERM US24/CNRS UMS3633, Paris, France., Baptista J; Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, United Kingdom.; Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom., Mahe MM; Université de Nantes, INSERM, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes, France., Hess MW; Institut für Histologie und Embryologie Medical University of Innsbruck, Innsbruck, Austria., Durel B; Cell Imaging Platform, INSERM-US24-CNRS UMS 3633 Structure Fédérative de Recherche Necker, Université Paris Cité, Paris, France., Lefort N; iPS Core Facility, Imagine Institute, INSERM U1163, Paris Descartes University, Paris, France., Banal C; iPS Core Facility, Imagine Institute, INSERM U1163, Paris Descartes University, Paris, France., Parisot M; Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France., Talbotec C; Department of Pediatric Gastroenterology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, F-75015, Paris, France., Lacaille F; Department of Pediatric Gastroenterology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, F-75015, Paris, France., Ecochard-Dugelay E; Hopital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France., Demir AM; Ankara Child Health and Diseases, Training and Research Hospital, Pediatric Gastroenterology, Ankara, Turkey., Vogel GF; Universitätsklinik für Pädiatrie I and.; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Faivre L; Department of Pathology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, Paris, France., Rodrigues A; John Radcliffe Hospital, Oxford, United Kingdom., Fowler D; John Radcliffe Hospital, Oxford, United Kingdom., Janecke AR; Universitätsklinik für Pädiatrie I and., Müller T; Universitätsklinik für Pädiatrie I and., Huber LA; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria., Rodrigues-Lima F; Université Paris Cité, BFA, UMR 8251, CNRS, Paris, France., Ruemmele FM; Department of Pediatric Gastroenterology, Assistance Publique-Hopitaux de Paris, Hopital Necker-Enfants Malades, F-75015, Paris, France., Uhlig HH; Translational Gastroenterology Unit and Department of Paediatrics, John Radcliffe Hospital, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom., Del Bene F; Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, Paris, France., Michaux G; Université de Rennes, CNRS, Institut de Génétique et Développement de Rennes (IGDR)-UMR 6290, Rennes, France., Cerf-Bensussan N; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France., Parlato M; Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, Paris, France.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2022 May 16; Vol. 132 (10).
DOI: 10.1172/JCI154997
Abstrakt: Variants in the UNC45A cochaperone have been recently associated with a syndrome combining diarrhea, cholestasis, deafness, and bone fragility. Yet the mechanism underlying intestinal failure in UNC45A deficiency remains unclear. Here, biallelic variants in UNC45A were identified by next-generation sequencing in 6 patients with congenital diarrhea. Corroborating in silico prediction, variants either abolished UNC45A expression or altered protein conformation. Myosin VB was identified by mass spectrometry as client of the UNC45A chaperone and was found misfolded in UNC45AKO Caco-2 cells. In keeping with impaired myosin VB function, UNC45AKO Caco-2 cells showed abnormal epithelial morphogenesis that was restored by full-length UNC45A, but not by mutant alleles. Patients and UNC45AKO 3D organoids displayed altered luminal development and microvillus inclusions, while 2D cultures revealed Rab11 and apical transporter mislocalization as well as sparse and disorganized microvilli. All those features resembled the subcellular abnormalities observed in duodenal biopsies from patients with microvillus inclusion disease. Finally, microvillus inclusions and shortened microvilli were evidenced in enterocytes from unc45a-deficient zebrafish. Taken together, our results provide evidence that UNC45A plays an essential role in epithelial morphogenesis through its cochaperone function of myosin VB and that UNC45A loss causes a variant of microvillus inclusion disease.
Databáze: MEDLINE