WDR83OS

WDR83OS encodes Asterix (originally PAT-10), an endoplasmic reticulum translocon-associated chaperone that engages specific transmembrane segments of polytopic membrane proteins during their co-translational membrane integration (PMID:12475939). Site-specific cross-linking of nascent opsin chains established that Asterix remains selectively and persistently adjacent to particular TM segments — the first transmembrane domain and, with prolonged engagement, TM5 — while ignoring others such as TM2 and TM4, demonstrating that it discriminates among TM helices rather than acting indiscriminately (PMID:12475939, PMID:18248332). Asterix heterodimerizes with CCDC47 to form the PAT (protein associated with the ER translocon) complex, which functions to ensure proper folding of large transmembrane-domain-containing client proteins (PMID:39471804); consistent with this chaperone role, loss of WDR83OS reduces expression of the multipass channel TRPC6, with which it physically interacts alongside TMEM208 (PMID:31266804). Biallelic loss-of-function variants in WDR83OS cause a human neurodevelopmental disorder with hypercholanemia, and zebrafish lacking the gene show defects in nervous system development, craniofacial development, and lipid absorption (PMID:39471804).

1. 2002 High

   Established that an uncharacterized translocon-associated factor (PAT-10/WDR83OS) selectively engages defined transmembrane segments of a nascent polytopic protein, framing it as a segment-specific component of membrane protein biogenesis rather than a general translocon subunit.

   Evidence Site-specific cross-linking of nascent opsin at the ER translocon with Sec61 co-IP and glycosylation-independence controls

   PMID:12475939

   Open questions at the time

   • Did not identify the molecular identity of the chaperone activity or its binding partners
   • Limited to opsin TM1; generality across other substrates untested
   • Functional consequence of the association for folding not measured
2. 2008 High

   Extended the selectivity model by showing prolonged engagement with opsin TM5 but rapid TM4 exit, demonstrating that segment discrimination follows the substrate's folding subdomains.

   Evidence Site-specific cross-linking of nascent opsin with TM7 hydrophobicity-substitution controls

   PMID:18248332

   Open questions at the time

   • Determinants of which TM segments are engaged remain undefined
   • No structural model of the engagement
   • Did not connect the activity to a named protein complex
3. 2019 Medium

   Linked WDR83OS to a functional outcome by showing it is required for expression of a client multipass channel and physically associates with that client and TMEM208, embedding it in an ER translocation complex.

   Evidence Genome-wide CRISPR/Cas9 screen plus co-IP of WDR83OS with TRPC6 and TMEM208, with TRPC6 protein-level readout

   PMID:31266804

   Open questions at the time

   • Single lab, two orthogonal methods without reciprocal validation
   • Whether interaction is direct vs. complex-mediated not resolved
   • Stoichiometry and architecture of the complex not defined
4. 2024 Medium

   Resolved the molecular identity and clinical relevance: WDR83OS encodes the 106-aa Asterix protein that heterodimerizes with CCDC47 as the PAT complex, and biallelic loss causes a human neurodevelopmental disorder with hypercholanemia recapitulated in zebrafish.

   Evidence Family-based exome sequencing with GeneMatcher case matching, zebrafish loss-of-function model, and biochemical characterization of the Asterix–CCDC47 heterodimer

   PMID:39471804

   Open questions at the time

   • Single publication for the disease association
   • Mechanistic link between PAT chaperone defect and hypercholanemia/lipid phenotype not established at molecular level
   • Full client repertoire of the PAT complex in vivo undefined

• How Asterix recognizes specific transmembrane segments and how its chaperone failure produces the tissue-specific phenotypes (neurodevelopment, bile/lipid homeostasis) remains unresolved.
• No structural basis for TM-segment selectivity
• Causal chain from chaperone loss to hypercholanemia unmapped
• Comprehensive client substrate list not defined