WHRN (whirlin, Q9P202) — research notes

Reviewer journal for the annotation review (2026-09-04, annotation-reviewer agent).

Gene identity

• HGNC symbol WHRN (formerly DFNB31; KIAA1526), 9q32; UniProt Q9P202, 907 aa canonical.
• Multi-PDZ scaffold: HHD1/HNL1–PDZ1–PDZ2–HHD2/HNL2–proline-rich–PDZ3–C-terminal PDZ-binding
  motif (UniProt features; deep research: Mathur & Yang 2019, Hearing Research).
• Alternative promoters/splicing produce long (full-length), N-terminal, and short (C-terminal)
  isoforms. Long isoform carries PDZ1+PDZ2 (needed for USH2/ankle-link and retinal roles);
  short isoform retains HHD2–PDZ3–PBM (tip complex role).

Two spatially/temporally distinct hair-cell roles

1. Ankle-link / USH2 complex (long isoform, developing bundles, stereocilia base).
   Quaternary complex WHRN–PDZD7–USH2A–ADGRV1(GPR98/VLGR1b):
   PMID:25406310 and PMID:25406310. Localization:
   PMID:25406310.
   Founding interaction paper: PMID:16434480. Note the ankle link fiber itself (GO:0002141) is
   extracellular (USH2A/ADGRV1 ectodomains); whirlin belongs to the cytoplasmic ankle-link
   complex (GO:0002142) — basis for the MODIFY calls on GO:0002141.
   Recent mechanism (deep research, not in GOA refs): Wang et al. 2023 Nat Commun
   (10.1038/s41467-023-37267-5) — the four-protein assembly is a phase-separated condensate;
   WHRN A64D/R223H impair self-association and LLPS; high ADGRV1 dissolves the condensate,
   a plausible mechanism for ankle-link disappearance ~P12 in mouse.

2. Stereocilia tip complex (short isoform, elongation). WHRN–MYO15A–EPS8 tip complex
   controls stereocilia elongation; MYO15A delivers whirlin to tips (UniProt SUBUNIT).
   PMID:16434480. CIB2 interacts with whirlin at tips:
   PMID:23023331, though whirlin is not required for CIB2 tip
   localization PMID:23023331. Lin et al. 2021 Cell Rep
   (10.1016/j.celrep.2021.108770; deep research) showed the tip complex phase-separates and
   condensation enhances EPS8-mediated F-actin bundling.

Retina

• Periciliary membrane complex (PMC) at the inner segment apex, around the connecting cilium:
  PMID:25406310; whirlin recruits its partners there:
  PMID:25406310.
• Connecting cilium / OLM: PMID:16434480.
• MPP1/p55 link to the Crumbs complex: PMID:17584769; co-localization at
  PMID:17584769 — supports basal body and synapse CC annotations (non-core).

Human genetics (wild-type function inferred from patients)

• USH2D (long-isoform mutations → deafness + RP): PMID:17171570; PMID:17171570; PMID:17171570
• DFNB31 nonsyndromic deafness: C-terminal/3' variants disrupting tip-complex function
  (deep research: Mathur & Yang 2019; mouse whirler = short stereocilia, profound deafness,
  no retinal degeneration).
• Genotype–phenotype: isoform-position model is probabilistic, not absolute (deep research).

Other reported sites/roles (non-core)

• Synapses of photoreceptors and OHCs: PMID:16434480
• Developing brain expression: PMID:16434480 — background
  for the Ensembl-transferred cerebellar Purkinje cell layer formation annotation (kept non-core).
• Paranodal junction maintenance (mouse; James Green 2013 thesis per deep research): paranodal
  decompaction/axonal swellings in Whrn-deficient mice, conduction largely normal — non-core.
• CASK: whirlin peptide (pSer685) binds CASK SH3-GK phospho-dependently
  PMID:22117215.

Curation decisions of note

• All bare GO:0005515 "protein binding" IPIs: none endorsed as-is. MODIFY → GO:0030674
  protein-macromolecule adaptor activity for the mechanistically central direct interactions
  (PMID:16434480 USH2A/ADGRV1; PMID:17584769 MPP1); MARK_AS_OVER_ANNOTATED for high-throughput
  or ligand-side evidence (PMID:12421765 KIAA Y2H; PMID:32296183 HuRI; PMID:36115835
  fragmentomics — source of >400 GOA lines; PMID:22117215 CASK; PMID:23023331 CIB2).
• GO:0042802 identical protein binding ACCEPTed: self-association is mechanistically core
  (homooligomers per UniProt; LLPS multivalency per Wang 2023/Lin 2021).
• GO:0002141 stereocilia ankle link (located_in/part_of; ISS+IEA) → MODIFY to GO:0002142:
  whirlin is in the cytoplasmic complex, not the extracellular link fiber.
• GO:0050910 detection of mechanical stimulus... → MARK_AS_OVER_ANNOTATED (whirlin acts
  upstream via stereocilium organization, not in the transduction event).
• GO:0060113 inner ear receptor cell differentiation (NAS) → MODIFY to GO:0060122 (the
  developmental role is specifically stereocilium organization).
• GO:0045184 establishment of protein localization (ISS) → MODIFY to GO:0072659 (whirlin
  recruits USH2A/ADGRV1 to specific plasma-membrane domains).
• GO:0005884 actin filament (IEA) → MARK_AS_OVER_ANNOTATED (localizes to actin-rich
  stereocilia, not an actin-filament component).
• Human IMPs from PMID:17171570 (retina homeostasis, sound, light) ACCEPTed — patient-based
  IMP is acceptable for wild-type function.