Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation

Andrea Accogli, Saurabh Shakya, Taewoo Yang, Christine Insinna, Soo Yeon Kim, David Bell, Kirill R. Butov, Mariasavina Severino, Marcello Niceta, Marcello Scala, Hyun Sik Lee, Taekyeong Yoo, Jimmy Stauffer, Huijie Zhao, Chiara Fiorillo, Marina Pedemonte, Maria C. Diana, Simona Baldassari, Viktoria Zakharova, Anna Shcherbina, Yulia Rodina, Christina Fagerberg, Laura Sønderberg Roos, Jolanta Wierzba, Artur Dobosz, Amanda Gerard, Lorraine Potocki, Jill A. Rosenfeld, Seema R. Lalani, Tiana M. Scott, Daryl Scott, Mahshid S. Azamian, Raymond Louie, Hannah W. Moore, Neena L. Champaigne, Grace Hollingsworth, Annalaura Torella, Vincenzo Nigro, Rafal Ploski, Vincenzo Salpietro, Federico Zara, Simone Pizzi, Giovanni Chillemi, Marzia Ognibene, Erin Cooney, Jenny Do, Anders Linnemann, Martin J. Larsen, Suzanne Specht, Kylie J. Walters, Hee-Jung Choi, Murim Choi, Marco Tartaglia, Phillippe Youkharibache, Jong-Hee Chae, Valeria Capra, Sung-Gyoo Park () and Christopher J. Westlake ()
Additional contact information
Andrea Accogli: McGill University Health Centre (MUHC)
Saurabh Shakya: National Institutes of Health
Taewoo Yang: Seoul National University
Christine Insinna: National Institutes of Health
Soo Yeon Kim: Seoul National University Hospital
David Bell: Frederick National Laboratory for Cancer Research
Kirill R. Butov: Oncology and Immunology
Mariasavina Severino: IRCCS Istituto Giannina Gaslini
Marcello Niceta: IRCCS
Marcello Scala: Università Degli Studi di Genova
Hyun Sik Lee: Seoul National University
Taekyeong Yoo: Seoul National University College of Medicine
Jimmy Stauffer: National Institutes of Health
Huijie Zhao: National Institutes of Health
Chiara Fiorillo: Università Degli Studi di Genova
Marina Pedemonte: IRCCS Istituto Giannina Gaslini
Maria C. Diana: IRCCS Istituto Giannina Gaslini
Simona Baldassari: IRCCS Istituto Giannina Gaslini
Viktoria Zakharova: Clinical data analysis department
Anna Shcherbina: Oncology and Immunology
Yulia Rodina: Oncology and Immunology
Christina Fagerberg: Odense University Hospital
Laura Sønderberg Roos: Copenhagen University Hospital
Jolanta Wierzba: Medical University of Gdansk
Artur Dobosz: Jagiellonian University Medical College
Amanda Gerard: Texas Children’s Hospital
Lorraine Potocki: Texas Children’s Hospital
Jill A. Rosenfeld: Baylor College of Medicine
Seema R. Lalani: Texas Children’s Hospital
Tiana M. Scott: University of Utah School of Medicine
Daryl Scott: Baylor Genetics Laboratories
Mahshid S. Azamian: Baylor Genetics Laboratories
Raymond Louie: Greenwood Genetic Center
Hannah W. Moore: Greenwood Genetic Center
Neena L. Champaigne: Greenwood Genetic Center
Grace Hollingsworth: Greenwood Genetic Center
Annalaura Torella: Telethon Institute of Genetics and Medicine (TIGEM)
Vincenzo Nigro: Telethon Institute of Genetics and Medicine (TIGEM)
Rafal Ploski: Medical University of Warsaw
Vincenzo Salpietro: University. College London
Federico Zara: Università Degli Studi di Genova
Simone Pizzi: IRCCS
Giovanni Chillemi: University of Tuscia, Via S. Camillo de Lellis s.n.c
Marzia Ognibene: IRCCS Istituto Giannina Gaslini
Erin Cooney: University of Texas Medical Branch
Jenny Do: University of Texas Medical Branch
Anders Linnemann: Odense University Hospital
Martin J. Larsen: Odense University Hospital
Suzanne Specht: National Institutes of Health
Kylie J. Walters: National Institutes of Health
Hee-Jung Choi: Seoul National University
Murim Choi: Seoul National University College of Medicine
Marco Tartaglia: IRCCS
Phillippe Youkharibache: National Institutes of Health
Jong-Hee Chae: Seoul National University Hospital
Valeria Capra: DINOGMI University of Genova
Sung-Gyoo Park: Seoul National University
Christopher J. Westlake: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract WDR44 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.

Date: 2024
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DOI: 10.1038/s41467-023-44611-2

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