tmc2a notes (Danio rerio, transmembrane channel-like 2a; UniProt E7FFT2)

2026-09-28 — session log (DANRE_DUPLICATION batch 3, random TGD_tree sample)

Deep research: not available for this gene (Edison/Falcon returns 402 Payment Required; the OpenAI key
is invalid). Not attempted, per instructions. No -deep-research-*.md file exists; the literature search was
done by hand (Europe PMC query (tmc2a OR tmc2b) AND zebrafish, 49 hits; cached the primary papers listed
below). Shared pair material is also in ../tmc2b/tmc2b-notes.md.

Accession E7FFT2 (Swiss-Prot TMC2A_DANRE, 916 aa), ZFIN:ZDB-GENE-060526-280, Ensembl ENSDARG00000033104,
chr5:55.22 Mb. Paralog tmc2b (F1QZE9, ZDB-GENE-060526-262) is also on chr5, at 25.62 Mb, 5 kb from tmc1.

Origin of the pair

• Maeda 2014 named the pair: PMID:25114259
• All three tmc1/2 genes on chr5: PMID:25114259
• Zhu 2020 attributes the pair to the TGD (citation, not an analysis): PMID:33490059
• My analysis (tmc2a-bioinformatics/RESULTS.md): Ensembl Compara places the duplication at Osteoglossocephalai;
  one gar orthologue for both. Both copies sit in segments whose genes map to human 9q21 (the TMC1 region) and
  to gar LG2. The gar TMC2 anchor is on LG2 near the gar orthologues of the tmc2b neighbourhood; the tmc2a
  neighbourhood maps to LG2 but farther from the anchor. Same zebrafish chromosome for both copies is unusual
  for TGD ohnologs; see RESULTS.md.

Protein

• 68% identity to tmc2b (compare_pair.py); 71.8% to gar TMC2 vs 67.2% for tmc2b (my script): tmc2b has
  diverged slightly more from the outgroup sequence.
• N-terminus binds Pcdh15a cytoplasmic domain (Y2H, co-IP): PMID:25114259
• Dominant-negative N-terminal fragment: PMID:25114259
• A Tmc2a-mEGFP transgene failed to express, so no Tmc2a localization or rescue data exist: PMID:32371604

Expression

• Inner ear from 1 dpf: PMID:25114259
• Ear-biased: PMID:25114259
• Lateral line: low; PMID:29269857
• Only in P-to-A hair cells of neuromasts: PMID:36905930
• Striolar/central zones of ear, upper crista layer: PMID:38035267
• Ear gene repressed by prdm1a in lateral line: PMID:40825768
• mRNA stability controlled by Esrp1/2 (tmc2b not): PMID:40086870

Function (mutants)

• Alleles: cwr3 (CRISPR, exon 6, 2-bp del, PTC; Chou 2017), cwr6/cwr7 (Chen/Zhu), Ex4 −23bp (TALEN; Smith 2020).
• Lateral line: double tmc2a/tmc2b abolishes MET; residual in tmc2b single depends on tmc2a: PMID:29269857
• Hearing: tmc2a single mutant reduces saccular microphonics: PMID:32371604
• PMID:32371604
• Crista upper layer (teardrop cells) needs Tmc2a: PMID:32371604
• Utricle high-frequency sensitivity: PMID:37952940
• Neuromast asymmetry lost without tmc2a: PMID:36905930
• No paralog upregulation in tmc1 mutants PMID:32167554; none in tmc2b mutants PMID:29269857
• Cross-rescue: Tmc2b-mEGFP rescues all end organs of tmc1/2a/2b triple mutants PMID:32371604. No reciprocal Tmc2a transgene exists.

Annotation decisions (summary)

• Voltage-gated calcium channel IBA: MODIFY to GO:0140135 (mechanically gated), as in the human TMC1 review.
• protein binding IPI (Pcdh15a): MODIFY to cadherin binding (GO:0045296); Pcdh15a is a cadherin-superfamily tip-link protein and the binding is mapped to the Tmc2a N-terminus.
• IEP development terms (lateral line development, inner ear receptor cell development): REMOVE; expression is not
  participation, and hair bundles develop normally in tmc triple mutants.
• GO:0050910 IGI from Chou 2017 (lateral line data only): MODIFY to GO:0050974.