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ZMYND12

Zinc finger MYND domain-containing protein 12 · UniProt Q9H0C1

Length
365 aa
Mass
41.8 kDa
Annotated
2026-06-11
6 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZMYND12 is an axonemal inner dynein arm (IDA) subunit required for flagellar and ciliary motility and male fertility (PMID:37934199, PMID:39066891). It assembles into a conserved axonemal complex with TTC29 and DNAH1, and loss of ZMYND12 in sperm from patients carrying homozygous ZMYND12 variants disrupts the proper localization of IDA-associated components DNAH1, DNALI1, WDR66, and TTC29; the TbTAX-1–TTC29 interaction and motility requirement are conserved in Trypanosoma brucei (PMID:37934199). In Zmynd12 knockout mice, ZMYND12 co-immunoprecipitates with TTC29 and PRKACA, and its loss reduces PRKACA abundance in sperm, linking ZMYND12 to impaired capacitation alongside reduced sperm motile velocity and subfertility (PMID:39066891). Loss of zmynd12 in zebrafish produces ciliary phenotypes, indicating a broader role in cilia-associated biology beyond the sperm flagellum (PMID:36533556). Homozygous ZMYND12 variants cause human male infertility (PMID:37934199).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2022 Medium

    Before any direct functional characterization, it was unknown whether ZMYND12 acted in motile cilia; in vivo loss-of-function established a ciliary requirement.

    Evidence CRISPR/Cas9 F0 crispant zebrafish with ciliary phenotype analysis

    PMID:36533556

    Open questions at the time
    • Phenotype described only briefly within a broader multi-gene screen
    • No molecular interactors or axonemal placement defined
    • Does not address the sperm flagellum specifically
  2. 2023 High

    The molecular context of ZMYND12 was unresolved; reciprocal interaction mapping and patient sperm imaging placed it in a defined axonemal complex whose loss mislocalizes IDA components.

    Evidence Whole-exome sequencing of infertile patients, patient sperm immunofluorescence, Co-IP and expansion microscopy plus RNAi in T. brucei, and comparative proteomics in Ttc29 KO mice

    PMID:37934199

    Open questions at the time
    • Stoichiometry and structural arrangement of the ZMYND12–TTC29–DNAH1 complex not resolved
    • Mechanism by which ZMYND12 directs DNAH1/DNALI1/WDR66 localization not defined
  3. 2024 High

    The cellular and signaling consequence of ZMYND12 loss was unknown; a knockout mouse tied ZMYND12 to IDA function, sperm beating, and a PRKACA-dependent capacitation defect.

    Evidence CRISPR/Cas9 knockout mice with fertility/motility assays, Co-IP/MS partner identification, and western blot for PRKACA

    PMID:39066891

    Open questions at the time
    • Mechanism linking ZMYND12 to PRKACA stability not established
    • Direct versus indirect nature of the ZMYND12–PRKACA interaction unresolved
    • Whether the capacitation defect is separable from the motility defect is unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZMYND12 mechanistically templates IDA assembly and stabilizes PRKACA within the flagellar axoneme remains open.
  • No structural model of the ZMYND12–TTC29–DNAH1 complex
  • Biochemical basis for PRKACA abundance control unknown
  • No molecular activity assigned to ZMYND12 itself

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1474165 Reproduction 2
Partners
DNAH1PRKACATTC29
Complex memberships
ZMYND12–TTC29–DNAH1 axonemal complexaxonemal inner dynein arm

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 ZMYND12 is part of an axonemal complex together with TTC29 and DNAH1, required for flagellum function and assembly. In patients with homozygous ZMYND12 variants, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29 in sperm cells. Co-immunoprecipitation and ultrastructure expansion microscopy in Trypanosoma brucei (using the ortholog TbTAX-1) confirmed a TbTAX-1–TTC29 complex, and comparative proteomics with Ttc29 KO mice identified DNAH1 as a third complex member. RNAi knockdown of TbTAX-1 dramatically impaired flagellar motility. Whole-exome sequencing in infertile patients; immunofluorescence in patient sperm; co-immunoprecipitation and ultrastructure expansion microscopy in T. brucei; RNAi knockdown in T. brucei; comparative proteomics in Ttc29 KO mice eLife High 37934199
2024 ZMYND12 is an inner dynein arm (IDA) subunit essential for sperm flagellar beating and male fertility. CRISPR/Cas9 Zmynd12 knockout mice showed male subfertility, reduced sperm motile velocity, and impaired capacitation. Co-immunoprecipitation and mass spectrometry identified TTC29 and PRKACA as ZMYND12-interacting proteins; PRKACA protein levels were decreased in Zmynd12−/− sperm, suggesting that loss of ZMYND12 reduces PRKACA abundance and thereby impairs capacitation. CRISPR/Cas9 knockout mouse generation; fertility and motility assays; co-immunoprecipitation combined with mass spectrometry; western blot for PRKACA levels Cellular and molecular life sciences : CMLS High 39066891
2022 Loss of zmynd12 function in zebrafish F0 crispants (CRISPR/Cas9 multiple-guide) produces ciliary phenotypes, establishing a role for ZMYND12 in cilia-associated biology in vivo. CRISPR/Cas9 F0 crispant zebrafish; ciliary phenotype analysis Disease models & mechanisms Medium 36533556

Source papers

Stage 0 corpus · 6 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. Disease models & mechanisms 17 36533556
2023 Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function. eLife 14 37934199
2022 A genome-wide association study on frequent exacerbation of asthma depending on smoking status. Respiratory medicine 10 35606283
2024 ZMYND12 serves as an IDAd subunit that is essential for sperm motility in mice. Cellular and molecular life sciences : CMLS 3 39066891
2026 Selection signatures on the autosomes and the X chromosome in the prolific Belclare sheep breed. Veterinary and animal science 0 42039311
2025 Polystyrene Nanoparticles Induce Transcriptional Repression in TM4 Sertoli Cells. Journal of applied toxicology : JAT 0 40926514

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