Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
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Published:2024-01-08
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Accogli Andrea, Shakya SaurabhORCID, Yang Taewoo, Insinna Christine, Kim Soo Yeon, Bell David, Butov Kirill R., Severino Mariasavina, Niceta MarcelloORCID, Scala MarcelloORCID, Lee Hyun SikORCID, Yoo Taekyeong, Stauffer Jimmy, Zhao HuijieORCID, Fiorillo Chiara, Pedemonte Marina, Diana Maria C., Baldassari Simona, Zakharova ViktoriaORCID, Shcherbina Anna, Rodina Yulia, Fagerberg ChristinaORCID, Roos Laura Sønderberg, Wierzba Jolanta, Dobosz Artur, Gerard Amanda, Potocki Lorraine, Rosenfeld Jill A.ORCID, Lalani Seema R., Scott Tiana M., Scott DarylORCID, Azamian Mahshid S.ORCID, Louie Raymond, Moore Hannah W., Champaigne Neena L., Hollingsworth Grace, Torella Annalaura, Nigro Vincenzo, Ploski Rafal, Salpietro VincenzoORCID, Zara FedericoORCID, Pizzi Simone, Chillemi GiovanniORCID, Ognibene MarziaORCID, Cooney Erin, Do Jenny, Linnemann Anders, Larsen Martin J.ORCID, Specht Suzanne, Walters Kylie J.ORCID, Choi Hee-JungORCID, Choi MurimORCID, Tartaglia MarcoORCID, Youkharibache Phillippe, Chae Jong-Hee, Capra Valeria, Park Sung-GyooORCID, Westlake Christopher J.ORCID
Abstract
AbstractWDR44 prevents ciliogenesis initiation by regulating RAB11-dependent vesicle trafficking. Here, we describe male patients with missense and nonsense variants within the WD40 repeats (WDR) of WDR44, an X-linked gene product, who display ciliopathy-related developmental phenotypes that we can model in zebrafish. The patient phenotypic spectrum includes developmental delay/intellectual disability, hypotonia, distinct craniofacial features and variable presence of brain, renal, cardiac and musculoskeletal abnormalities. We demonstrate that WDR44 variants associated with more severe disease impair ciliogenesis initiation and ciliary signaling. Because WDR44 negatively regulates ciliogenesis, it was surprising that pathogenic missense variants showed reduced abundance, which we link to misfolding of WDR autonomous repeats and degradation by the proteasome. We discover that disease severity correlates with increased RAB11 binding, which we propose drives ciliogenesis initiation dysregulation. Finally, we discover interdomain interactions between the WDR and NH2-terminal region that contains the RAB11 binding domain (RBD) and show patient variants disrupt this association. This study provides new insights into WDR44 WDR structure and characterizes a new syndrome that could result from impaired ciliogenesis.
Funder
U.S. Department of Health & Human Services | National Institutes of Health
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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