TEDC1

TEDC1 is a centrosomal protein that forms a tetrameric complex with TEDC2, delta-tubulin, and epsilon-tubulin, and is essential for the assembly of triplet microtubules and structural integrity of centrioles (PMID:40067174). Within this complex, TEDC1 and TEDC2 constitute a subcomplex whose formation requires the TEDC1 C-terminus, and all four subunits are mutually dependent for centrosomal localization; loss of TEDC1 produces centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins such as POC5, and a cycle of centriole elongation, fragmentation, and disintegration during mitosis (PMID:40067174, PMID:39979680). TEDC1 deficiency also causes cell cycle abnormalities, reduced acetylated tubulin levels, and cilia defects, and biallelic loss-of-function variants cause a syndromic disorder featuring primary microcephaly, cranial bone dysplasia, and sterility, as demonstrated in patient cells and tedc1-knockout zebrafish (PMID:39979680, PMID:30842647).

1. 2019 Low

   Establishing that TEDC1 is disease-relevant: exome sequencing in microcephaly patients identified TEDC1 as a candidate centrosome-pathway gene, linking it for the first time to a human developmental disorder.

   Evidence Exome sequencing with functional studies in a primary microcephaly cohort

   PMID:30842647

   Open questions at the time

   • Mechanistic detail of how TEDC1 variants cause microcephaly was not provided
   • No binding partners or protein complex defined at this stage
   • Single cohort without independent replication
2. 2025 High

   Defining the molecular complex: TEDC1 physically associates with TEDC2, delta-tubulin, and epsilon-tubulin as a tetramer, with TEDC1–TEDC2 forming an independent subcomplex, resolving the compositional basis of the delta/epsilon-tubulin pathway.

   Evidence Reciprocal co-immunoprecipitation, subcomplex reconstitution in absence of tubulins, AlphaFold Multimer structural modeling (eLife)

   PMID:40067174

   Open questions at the time

   • No experimentally determined atomic-resolution structure of the tetramer
   • Stoichiometry and assembly order of the complex in vivo remain undefined
   • Direct contacts between TEDC1 and delta/epsilon-tubulin versus TEDC2-mediated bridging not fully resolved
3. 2025 High

   Establishing the ultrastructural function: loss of TEDC1 or TEDC2 eliminates triplet microtubules from centrioles, prevents recruitment of the central core scaffold (POC5), and causes centriole disintegration during mitosis, demonstrating that the tetramer is required for centriole architectural integrity.

   Evidence CRISPR knockout cell lines analyzed by ultrastructure expansion microscopy and immunofluorescence (eLife)

   PMID:40067174

   Open questions at the time

   • Whether TEDC1 directly stabilizes the C-tubule or acts indirectly through tubulin modification is unknown
   • Temporal sequence of triplet loss versus scaffold recruitment failure not resolved
4. 2025 Medium

   Mapping a functional domain and organismal phenotype: a patient-derived C-terminal truncation of TEDC1 disrupts TEDC2 binding, and tedc1-knockout zebrafish recapitulate growth impairment, cranial bone dysplasia, cilia defects, and sterility, linking the molecular interaction to disease pathophysiology.

   Evidence Binding assay with frameshift-truncated TEDC1, patient cell cycle analysis, CRISPR tedc1−/− zebrafish (EJHG)

   PMID:39979680

   Open questions at the time

   • Precise residues mediating the TEDC1–TEDC2 interface beyond the C-terminal region are not mapped
   • Whether cilia defects are a direct consequence of triplet loss or a secondary effect of centriole disintegration is unclear
   • Only a single truncation variant tested; contribution of other domains untested

• Key unresolved question: how the TEDC1-containing tetramer mechanistically promotes C-tubule assembly and whether it acts catalytically, as a structural template, or by recruiting additional factors remains unknown.
• No biochemical reconstitution of triplet microtubule assembly with purified tetramer
• No high-resolution experimental structure of the TEDC1–TEDC2–tubulin complex
• Relationship between TEDC1 loss and the specific cell cycle arrest checkpoint is undefined