CPLANE1

CPLANE1 (C5orf42/JBTS17) is a cilia transition zone component required for ciliogenesis and the assembly of a functional primary cilium that supports Hedgehog signaling, cell polarity, and directional migration (PMID:25877302, PMID:35582950). At the transition zone it acts upstream of the Joubert syndrome-associated proteins NPHP1 and CEP290, whose localization is lost when CPLANE1 is mutated (PMID:25877302). Through the primary cilium it is required for Sonic Hedgehog pathway responsiveness: patient fibroblasts and knockdown cells show diminished response to SHH/Hh agonists, and the defect is reversed by the pathway activator SAG (PMID:29321670, PMID:35582950). Loss of CPLANE1 function impairs establishment of cell polarity and directional cell migration, and in developing embryos causes cerebellar foliation defects, facial midline widening, axonal pathfinding errors, and abnormal dorsal root ganglia development (PMID:25877302, PMID:29321670, PMID:39694173). Beyond the cilium, CPLANE1 has an extraciliary mitotic role: it localizes to the kinetochore in a cell-cycle-dependent, proteolytically regulated manner, interacts with LIS1 and influences its localization, and is required for chromosome alignment, spindle orientation, and mitotic progression of neural progenitors (PMID:31004438). Biallelic loss-of-function mutations in CPLANE1 cause Joubert syndrome (JBTS17) and the allelic Oral-Facial-Digital syndrome type VI, with at least one variant acting through splice disruption and nonsense-mediated mRNA decay (PMID:22425360, PMID:24178751, PMID:40074699).

1. 2012 High

   Established CPLANE1 as a disease gene by linking biallelic loss-of-function mutations to a defined human ciliopathy, framing all subsequent mechanistic work.

   Evidence Exome sequencing with Sanger validation across multiple French Canadian Joubert syndrome families, absent in 477 controls

   PMID:22425360

   Open questions at the time

   • Did not define the protein's subcellular localization or molecular function
   • No mechanism connecting mutation to cilia phenotype
2. 2013 High

   Extended the genetic spectrum by showing CPLANE1 mutations underlie the allelic disorder OFD VI, consolidating it as a core ciliopathy gene.

   Evidence Exome sequencing with Sanger confirmation across six unrelated OFD VI families

   PMID:24178751

   Open questions at the time

   • Genotype-phenotype basis for OFD VI vs Joubert presentation unresolved
   • No protein-level mechanism
3. 2015 High

   Localized the protein to the cilia transition zone and placed it upstream of NPHP1 and CEP290, providing the first molecular mechanism for the ciliopathy phenotype.

   Evidence Immunostaining, forward genetic screen and Hug mouse model, ciliogenesis and wound-healing assays in mouse and patient fibroblasts

   PMID:25877302

   Open questions at the time

   • Mode of transition zone recruitment unknown
   • Direct physical interaction with NPHP1/CEP290 not demonstrated
4. 2018 Medium

   Connected CPLANE1 loss to defective Sonic Hedgehog signaling, linking the ciliary defect to specific developmental phenotypes.

   Evidence siRNA knockdown in chicken embryos and SHH agonist response assay in patient fibroblasts

   PMID:29321670

   Open questions at the time

   • Step in the SHH cascade affected not pinpointed
   • Single-lab functional assay
5. 2019 High

   Uncovered an extraciliary mitotic function at the kinetochore and a LIS1 interaction, revealing a second pathway by which CPLANE1 affects neural development.

   Evidence Immunostaining, live imaging, siRNA knockdown in human cells and in utero electroporation in mouse cortex

   PMID:31004438

   Open questions at the time

   • Structural basis of the LIS1 interaction unknown
   • How a transition zone protein is targeted to the kinetochore unresolved
6. 2022 Medium

   Confirmed in an independent system that CPLANE1 supports ciliation, migration and Hh signaling, with rescue establishing the Hh defect as on-pathway.

   Evidence siRNA knockdown in NIH/3T3 cells with cilia counting, migration assay and Hh reporter with SAG rescue

   PMID:35582950

   Open questions at the time

   • Molecular target of CPLANE1 within the Hh pathway not identified
   • Single-lab study
7. 2024 Medium

   Extended the developmental requirement for CPLANE1 to peripheral nervous system patterning.

   Evidence Loss-of-function in chicken embryos with morphological analysis of dorsal root ganglia

   PMID:39694173

   Open questions at the time

   • Whether the DRG defect is ciliary or extraciliary not determined
   • Single organism model
8. 2025 Medium

   Demonstrated a specific loss-of-function mechanism in which a missense variant triggers exon skipping and NMD, refining how CPLANE1 mutations cause disease.

   Evidence RNA splicing analysis, mRNA stability assays and SMG1-inhibitor rescue in patient PBMCs

   PMID:40074699

   Open questions at the time

   • Generalizability to other CPLANE1 variants unknown
   • Single-lab study

• How CPLANE1 is recruited to both the transition zone and the kinetochore, and the structural and biochemical basis of its function at each site, remains unresolved.
• No structural model of CPLANE1 or its complexes
• Direct biochemical interactions with NPHP1/CEP290 not established
• Mechanism switching CPLANE1 between ciliary and mitotic roles unknown