人类纤毛病蛋白RSG1将CPLANE复合体与过渡区结构联系起来。
The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture.
作者信息
Vazquez Neftalí, Lee Chanjae, Valenzuela Irene, Phan Thao P, Derderian Camille, Chávez Marcelo, Mooney Nancie A, Demeter Janos, Aziz-Zanjani Mohammad Ovais, Cusco Ivon, Codina Marta, Martínez-Gil Núria, Valverde Diana, Solarat Carlos, Buel Ange-Line, Thauvin-Robinet Cristel, Steichen Elisabeth, Filges Isabel, Joset Pascal, De Geyter Julie, Vaidyanathan Krishna, Gardner Tynan P, Toriyama Michinori, Marcotte Edward M, Drew Kevin, Roberson Elle C, Jackson Peter K, Reiter Jeremy F, Tizzano Eduardo F, Wallingford John B
机构信息
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
Department of Clinical and Molecular Genetics, Vall d´Hebron University Hospital. European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA), Medicine Genetics Group, Vall d´Hebron Research Institute, Barcelona, Spain.
出版信息
Nat Commun. 2025 Jul 1;16(1):5701. doi: 10.1038/s41467-025-61005-8.
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.
纤毛是重要的细胞器，控制纤毛功能的基因变异会导致纤毛病。纤毛发生和平面极性效应器（CPLANE）蛋白复合物对纤毛发生至关重要，除了一个亚基外，CPLANE复合物的所有亚基都与人类纤毛病有关。在这里，我们鉴定了三个家系，其中剩余的CPLANE亚基CPLANE2/RSG1的变异也会导致纤毛病。这些患者表现出腭裂、舌叶状和多指畸形，这些是口面指综合征的特征性表型。我们进一步表明，这些等位基因破坏了纤毛发生的两个关键步骤，即基体对接和鞭毛内运输蛋白的募集。此外，APMS显示Rsg1以GTP依赖的方式结合CPLANE和过渡区蛋白Fam92。最后，我们表明CPLANE通常是正常过渡区结构所必需的。我们的工作证明CPLANE2/RSG1是人类纤毛病的致病基因，也为纤毛过渡区组装机制提供了新的线索。
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