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Title: Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
Authors: Accogli, Andrea
Shakya, Saurabh
Yang, Taewoo
Insinna, Christine
Kim, Soo Yeon
Bell, David
Butov, Kirill R
Severino, Mariasavina
Niceta, Marcello
Scala, Marcello
Lee, Hyun Sik
Yoo, Taekyeong
Stauffer, Jimmy
Zhao, Huijie
Fiorillo, Chiara
Pedemonte, Marina
Diana, Maria C
Baldassari, Simona
Zakharova, Viktoria
Shcherbina, Anna
Rodina, Yulia
Fagerberg, Christina
Roos, Laura Sønderberg
Wierzba, Jolanta
Dobosz, Artur
Gerard, Amanda
Potocki, Lorraine
Rosenfeld, Jill A
Lalani, Seema R
Scott, Tiana M
Scott, Daryl
Azamian, Mahshid S
Louie, Raymond
Moore, Hannah W
Champaigne, Neena L
Hollingsworth, Grace
Torella, Annalaura
Nigro, Vincenzo
Ploski, Rafal
Salpietro, Vincenzo
Zara, Federico
Pizzi, Simone
Chillemi, Giovanni 
Ognibene, Marzia
Cooney, Erin
Do, Jenny
Linnemann, Anders
Larsen, Martin J
Specht, Suzanne
Walters, Kylie J
Choi, Hee-Jung
Choi, Murim
Tartaglia, Marco
Youkharibache, Phillippe
Chae, Jong-Hee
Capra, Valeria
Park, Sung-Gyoo
Westlake, Christopher J
Issue Date: 2024
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.
ISSN: 2041-1723
DOI: 10.1038/s41467-023-44611-2
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