PUBLICATION

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

Authors
Accogli, A., Shakya, S., Yang, T., Insinna, C., Kim, S.Y., Bell, D., Butov, K.R., Severino, M., Niceta, M., Scala, M., Lee, H.S., Yoo, T., Stauffer, J., Zhao, H., Fiorillo, C., Pedemonte, M., Diana, M.C., Baldassari, S., Zakharova, V., Shcherbina, A., Rodina, Y., Fagerberg, C., Roos, L.S., Wierzba, J., Dobosz, A., Gerard, A., Potocki, L., Rosenfeld, J.A., Lalani, S.R., Scott, T.M., Scott, D., Azamian, M.S., Louie, R., Moore, H.W., Champaigne, N.L., Hollingsworth, G., Torella, A., Nigro, V., Ploski, R., Salpietro, V., Zara, F., Pizzi, S., Chillemi, G., Ognibene, M., Cooney, E., Do, J., Linnemann, A., Larsen, M.J., Specht, S., Walters, K.J., Choi, H.J., Choi, M., Tartaglia, M., Youkharibache, P., Chae, J.H., Capra, V., Park, S.G., Westlake, C.J.
ID
ZDB-PUB-240110-6
Date
2024
Source
Nature communications   15: 365365 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Brain
  • Ciliopathies*/genetics
  • Cognition
  • Humans
  • Male
  • WD40 Repeats*
  • Zebrafish/genetics
PubMed
38191484 Full text @ Nat. Commun.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping