CPLANE2

CPLANE2 (RSG1) is a small GTPase that functions as a core component of the CPLANE ciliogenesis complex, governing basal body maturation, intraflagellar transport (IFT) protein recruitment, and axonemal microtubule elongation during cilia initiation. It localizes to the mother centriole in a manner dependent on TTBK2, the CPLANE subunit INTU, and its own GTPase activity, and it binds the CPLANE complex components (INTU, FUZ, WDPCP, JBTS17) and the transition zone protein FAM92 in a GTP-dependent manner (PMID:29038301, PMID:40593758). A point mutation in the RSG1 GTP-binding pocket specifically blocks axonemal elongation without disrupting basal body docking or IFT protein localization, establishing that GTPase activity is required for a discrete downstream step after basal body maturation (PMID:38721990). Loss-of-function variants in CPLANE2 cause Oral-Facial-Digital Syndrome, a ciliopathy, with disease-associated mutations disrupting basal body docking and IFT recruitment (PMID:40593758, PMID:41952398).

1. 2013 Medium

   Establishing that RSG1 is required for ciliogenesis answered whether this uncharacterized small GTPase has a ciliary role, revealing its necessity for basal body apical trafficking, IFT dynamics, and cytoplasmic localization of the retrograde IFT-A protein IFT43.

   Evidence Morpholino knockdown in Xenopus multiciliated cells with live IFT imaging and basal body immunofluorescence

   PMID:24192041

   Open questions at the time

   • Morpholino-based knockdown requires genetic confirmation
   • Whether RSG1 GTPase activity is required was not tested
   • Mechanism linking RSG1 to IFT-A localization not defined
2. 2017 High

   Demonstrating that RSG1 localizes to the mother centriole and is required for a final maturation step enabling axonemal elongation resolved its site of action and placed it in a genetic pathway downstream of TTBK2 and INTU.

   Evidence Mouse Rsg1 knockout embryos with live imaging, immunofluorescence, and epistasis analysis with TTBK2 and INTU

   PMID:29038301

   Open questions at the time

   • Biochemical GTPase activity not directly measured
   • Direct physical interactions with CPLANE subunits not demonstrated
   • Whether the centriolar localization defect is the proximate cause of axonemal failure was not resolved
3. 2024 Medium

   A G1-domain point mutation that disrupts axonemal elongation without affecting basal body docking or IFT protein recruitment to the basal body demonstrated that RSG1 GTPase activity is specifically required for a post-docking step, separating its GTP-dependent function from its scaffolding role.

   Evidence Forward genetic screen in mouse; point mutation mapping with immunofluorescence of centrosomal and IFT proteins

   PMID:38721990

   Open questions at the time

   • In vitro GTPase activity and GTP/GDP binding kinetics not measured biochemically
   • Identity of the effector engaged by GTP-bound RSG1 at the basal body remains unknown
   • Single lab finding
4. 2024 Low

   Identification of patient variants in CPLANE2 causing Oral-Facial-Digital Syndrome established a direct human disease link, though the structural basis of pathogenicity relied on in silico modeling.

   Evidence Patient variant identification with in silico 3D structural modeling of FUZ–RSG1 interaction

   PMID:41952398

   Open questions at the time

   • No in vitro or cell-based validation of the predicted FUZ–RSG1 interaction disruption
   • Genotype-phenotype correlation not established across a patient cohort
   • Functional rescue experiments not performed
5. 2025 High

   APMS demonstrated that RSG1 binds the CPLANE complex and the transition zone protein FAM92 in a GTP-dependent manner, and that disease-causing variants disrupt basal body docking and IFT recruitment, unifying the GTPase-dependent interaction network with ciliopathy pathogenesis.

   Evidence Affinity purification mass spectrometry with GTP-dependence controls, patient-derived variant functional analysis, ciliogenesis assays

   PMID:40593758

   Open questions at the time

   • Direct structural basis of GTP-dependent FAM92 binding not resolved
   • Whether RSG1 acts catalytically (multiple GTP cycles) or as a molecular switch remains untested
   • Downstream effectors linking RSG1–FAM92 binding to axonemal elongation not identified
6. 2025 Medium

   Demonstration that folic acid-regulated reactive oxygen species modulate RSG1 GTPase activity and ciliogenesis connected a metabolic/environmental input to RSG1-dependent cilia formation, expanding the regulatory context.

   Evidence Mouse neural tube defect models with Rsg1 mutation, ROS measurements, and cilia formation assays under varying folic acid levels

   PMID:39755226

   Open questions at the time

   • Direct biochemical demonstration of ROS-mediated RSG1 GTPase modulation not shown
   • Relevant cysteine residues or redox-sensitive sites on RSG1 not identified
   • Specificity of the ROS effect to RSG1 versus other GTPases not established

• The identity of the downstream effector(s) through which GTP-bound RSG1 drives axonemal elongation after basal body docking, and whether RSG1 functions as a canonical molecular switch or has additional catalytic roles, remain unresolved.
• No effector protein identified downstream of GTP-bound RSG1
• No in vitro GTPase kinetics or structural data for RSG1
• Mechanism by which transition zone architecture depends on CPLANE/RSG1 is undefined