The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture

Neftalí Vazquez, Chanjae Lee, Irene Valenzuela, Thao P. Phan, Camille Derderian, Marcelo Chávez, Nancie A. Mooney, Janos Demeter, Mohammad Ovais Aziz-Zanjani, Ivon Cusco, Marta Codina, Núria Martínez-Gil, Diana Valverde, Carlos Solarat, Ange-Line Buel, Cristel Thauvin-Robinet, Elisabeth Steichen, Isabel Filges, Pascal Joset, Julie Geyter, Krishna Vaidyanathan, Tynan P. Gardner, Michinori Toriyama, Edward M. Marcotte, Kevin Drew, Elle C. Roberson, Peter K. Jackson, Jeremy F. Reiter, Eduardo F. Tizzano () and John B. Wallingford ()
Additional contact information
Neftalí Vazquez: University of Texas at Austin
Chanjae Lee: University of Texas at Austin
Irene Valenzuela: Vall d´Hebron Research Institute
Thao P. Phan: San Francisco
Camille Derderian: San Francisco
Marcelo Chávez: Stanford University School of Medicine
Nancie A. Mooney: Stanford University School of Medicine
Janos Demeter: Stanford University School of Medicine
Mohammad Ovais Aziz-Zanjani: Stanford University School of Medicine
Ivon Cusco: Vall d´Hebron Research Institute
Marta Codina: Vall d´Hebron Research Institute
Núria Martínez-Gil: Vall d´Hebron Research Institute
Diana Valverde: SERGASUVIGO
Carlos Solarat: SERGASUVIGO
Ange-Line Buel: University of Burgundy
Cristel Thauvin-Robinet: University of Burgundy
Elisabeth Steichen: University of Innsbruck
Isabel Filges: University Hospital Basel
Pascal Joset: University Hospital Basel
Julie Geyter: University Hospital Basel
Krishna Vaidyanathan: University of Texas at Austin
Tynan P. Gardner: University of Texas at Austin
Michinori Toriyama: Sanda
Edward M. Marcotte: University of Texas at Austin
Kevin Drew: University of Illinois at Chicago
Elle C. Roberson: CU Anschutz Medical Campus
Peter K. Jackson: Stanford University School of Medicine
Jeremy F. Reiter: San Francisco
Eduardo F. Tizzano: Vall d´Hebron Research Institute
John B. Wallingford: University of Texas at Austin

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Cilia are essential organelles, and variants in genes governing ciliary function result in ciliopathic diseases. The Ciliogenesis and PLANar polarity Effectors (CPLANE) protein complex is essential for ciliogenesis, and all but one subunit of the CPLANE complex have been implicated in human ciliopathy. Here, we identify three families in which variants in the remaining CPLANE subunit CPLANE2/RSG1 also cause ciliopathy. These patients display cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. We further show that these alleles disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins. Moreover, APMS reveals that Rsg1 binds CPLANE and the transition zone protein Fam92 in a GTP-dependent manner. Finally, we show that CPLANE is generally required for normal transition zone architecture. Our work demonstrates that CPLANE2/RSG1 is a causative gene for human ciliopathy and also sheds new light on the mechanisms of ciliary transition zone assembly.

Date: 2025
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DOI: 10.1038/s41467-025-61005-8

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