USH1C / harmonin (Q9Y6N9) — research notes

Reviewer journal for the annotation review (2026-09-04). Provenance is inline as
[PMID:NNN "quote"].

Identity and architecture

• USH1C encodes harmonin, historically also called PDZ-73, AIE-75, NY-CO-38/37 and
  NY-REN-3. It was identified as the USH1C disease gene in 2000
  PMID:10973247.
• Alternative splicing yields isoform classes a, b and c; the long b isoforms add a
  second coiled-coil and a PST (proline/serine/threonine-rich) actin-binding region
  PMID:10973247. The b isoforms are hair-bundle enriched; retinal expression
  is dominated by harmonin-a1 (Nagel-Wolfrum 2023, via deep research; not cached).
• Harmonin is not an enzyme/transporter/channel; it is a multivalent PDZ scaffold.
  The N-domain (HHD) plus PDZ1 form a supramodule
  PMID:20142502.

Hair-cell function (core)

• USH1C loss in humans causes congenital profound deafness, vestibular dysfunction
  and progressive retinitis pigmentosa
  PMID:10973247. Some alleles cause
  nonsyndromic deafness DFNB18 PMID:10973247.
• In the mouse inner ear, expression is hair-cell specific
  PMID:10973247.
• Harmonin belongs to BOTH hair-cell scaffolding complexes:
• The upper tip-link density (UTLD) of mature stereocilia, with MYO7A and
  SANS/USH1G, anchoring CDH23 at the upper tip-link insertion (tension-bearing).
  Deep research: "Harmonin-b is concentrated at the upper tip-link density of
  stereocilia... There it forms part of a CDH23–harmonin–SANS–MYO7A assembly that
  anchors mechanically loaded tip links to the actin core."
• The transient ankle-link/USH2 complex of developing bundles (USH2A, ADGRV1,
  whirlin, PDZD7). Deep research: "Harmonin PDZ1 recognizes C-terminal motifs in
  usherin/USH2A and ADGRV1, providing a physical bridge between USH1 and USH2
  networks." (Reiners 2005, PMID not cached here.)
• The harmonin–SANS complex is exceptionally stable and destabilized by USH1
  patient mutations [PMID:20142502 "the synergistic PDZ1/SAM and PDZ1/carboxyl PDZ
  binding-motif interactions, between harmonin and Sans, lock the two scaffold
  proteins into a highly stable complex" ... "Mutations in harmonin and Sans found
  in USH1 patients are shown to destabilize the complex formation of the two
  proteins."].

Intestinal brush border function (core)

• Harmonin is the shared scaffold between the Usher complex and the enterocyte
  intermicrovillar adhesion complex (IMAC: CDHR2, CDHR5, USH1C, ANKS4B, MYO7B)
  PMID:32209652.
• It binds protocadherin tails and promotes their tip targeting
  PMID:24725409; harmonin-null mice have severe brush border defects
  PMID:24725409. This explains the enteropathy seen in some USH1C patients
  PMID:32209652.
• USH1C sits at the top of the IMAC assembly hierarchy
  PMID:26812018.
• Earlier support: brush border proteome + CACO-2 immunostaining
  PMID:21330445; apical enrichment in intestinal
  epithelium was already seen in 1999
  PMID:10209257.
• Direct tip localization PMID:32209652.

Retina (genuine, secondary emphasis)

• USH1C patients develop retinitis pigmentosa (above). Harmonin protein detected in
  human rod outer segments, cone pedicles, Mueller glia endfeet/microvilli, and OLM
  junctions; harmonin-a1 is the dominant retinal transcript (Nagel-Wolfrum 2023 via
  deep research; not in cached publications).
• Spectrin betaV association along the photoreceptor trafficking route
  PMID:23704327.

Curation judgments of note

• PMID:11398101 (PCDH15/USH1F paper) is cited for three USH1C IMP annotations
  (GO:0007605, GO:0050953, GO:0045494). Full text contains no USH1C data — USH1C
  appears once, in the intro list of cloned USH1 genes. The terms themselves are
  clearly correct for USH1C (patient phenotype per PMID:10973247), so the
  annotations were ACCEPTed with the citation flagged as MISCITED in
  reference_review, rather than removed.
• PMID:15219944 (AIE-75 overexpression induces G2/M arrest in SW480 cells):
  recommended REMOVE for GO:0000086 "G2/M transition of mitotic cell cycle". The
  assay is ectopic overexpression in a cancer line lacking endogenous harmonin, the
  phenotype is arrest (not participation in the transition), and no subsequent
  literature supports a physiological cell-cycle role.
• GO:0050885 "neuromuscular process controlling balance" (ARBA IEA): the balance
  defect is vestibular-sensory, not neuromuscular; proposed MODIFY to GO:0050957
  equilibrioception (already annotated IMP from PMID:10973247).
• Bare GO:0005515 protein binding lines: MODIFY to GO:0030674
  protein-macromolecule adaptor activity for the three mechanistically informative
  papers (PMID:20142502 SANS; PMID:24725409 CDHR2/CDHR5/MYO7B; PMID:26812018
  ANKS4B/MYO7B); MARK_AS_OVER_ANNOTATED for the high-throughput interactome /
  fragmentomics lines (PMID:25416956, 25502805, 27173435, 28514442, 29997244,
  31515488, 32814053, 33961781, 36115835) and the isolated Y2H partners
  (PMID:11311560 MCC2; PMID:16464467 DOCK4).
• GO:0005929 cilium (IBA): stereocilia are actin-based protrusions, not cilia; kept
  as NON_CORE on the strength of photoreceptor ciliary-region reports and the
  patient-fibroblast primary-cilium rescue (deep research).
• Isoform note: GOA carries no isoform-specific or negated (NOT) annotation lines
  for USH1C, although the biology is isoform-structured (b isoforms in hair
  bundles, a1 in retina; UniProt records complex-specific isoform usage between the
  Usher complex and the IMAC).