{"gene":"ZMYND12","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2023,"finding":"ZMYND12 forms an axonemal complex with TTC29 and DNAH1, is required for flagellum function and assembly, and its localization to the axoneme was confirmed in the Trypanosoma brucei ortholog TbTAX-1; RNAi knockdown of TbTAX-1 dramatically impaired flagellar motility; in human patients with homozygous ZMYND12 variants, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29 in sperm cells.","method":"Co-immunoprecipitation, ultrastructure expansion microscopy, comparative proteomics (Trypanosoma and Ttc29 KO mice), RNAi knockdown, immunofluorescence in human sperm, whole-exome sequencing","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (Co-IP, proteomics, RNAi functional readout, expansion microscopy, human patient immunofluorescence) in a single study with rigorous controls","pmids":["37934199"],"is_preprint":false},{"year":2024,"finding":"ZMYND12 functions as a subunit of the inner dynein arm (IDA) complex in sperm flagella; it interacts with TTC29 and PRKACA, and ZMYND12 knockout mice exhibit reduced sperm motile velocity, impaired capacitation, and decreased PRKACA levels in sperm, indicating that ZMYND12 supports flagellar beating and capacitation through its association with PRKACA.","method":"CRISPR/Cas9 knockout mouse generation, co-immunoprecipitation, mass spectrometry, sperm motility and capacitation assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 1–2 — in vivo KO with defined phenotypic readout combined with Co-IP/MS identifying interacting partners and mechanistic link to PRKACA","pmids":["39066891"],"is_preprint":false},{"year":2022,"finding":"ZMYND12 is a cilia-associated gene; CRISPR/Cas9 F0 crispant embryos targeting zmynd12 in zebrafish recapitulate ciliary phenotypes, placing ZMYND12 in the category of genes required for cilia function.","method":"Multiple-guide CRISPR/Cas9 F0 crispant zebrafish screen with ciliary phenotype readout","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with defined ciliary phenotypic readout, but limited mechanistic resolution beyond functional requirement","pmids":["36533556"],"is_preprint":false}],"current_model":"ZMYND12 is an axonemal inner dynein arm (IDA) subunit that forms a complex with TTC29, DNAH1, and PRKACA to support flagellar/ciliary beating and assembly; loss of ZMYND12 disrupts localization of multiple IDA-associated proteins, impairs sperm motility and capacitation, and causes male infertility."},"narrative":{"teleology":[{"year":2022,"claim":"Whether ZMYND12 is required for cilia function in vivo was unknown; zebrafish F0 crispants targeting zmynd12 displayed ciliary phenotypes, establishing ZMYND12 as a cilia-associated gene with a conserved functional requirement.","evidence":"Multiple-guide CRISPR/Cas9 F0 crispant screen in zebrafish with ciliary phenotype readout","pmids":["36533556"],"confidence":"Medium","gaps":["No mechanistic resolution beyond a general requirement for cilia function","Molecular partners and subciliary localization were not identified","F0 crispant mosaicism limits quantitative phenotypic interpretation"]},{"year":2023,"claim":"The molecular context of ZMYND12 within the axoneme was undefined; co-immunoprecipitation, proteomics, and expansion microscopy demonstrated that ZMYND12 forms a complex with TTC29 and DNAH1, localizes to the axoneme, and is required for proper localization of multiple IDA subunits (DNAH1, DNALI1, WDR66, TTC29), with RNAi knockdown of the Trypanosoma ortholog confirming a conserved role in flagellar motility.","evidence":"Co-IP, comparative proteomics (Trypanosoma and Ttc29 KO mice), RNAi knockdown in T. brucei, ultrastructure expansion microscopy, immunofluorescence in human patient sperm, whole-exome sequencing","pmids":["37934199"],"confidence":"High","gaps":["Direct structural position of ZMYND12 within the IDA repeat was not resolved","The MYND zinc-finger domain's specific molecular function (e.g., protein–protein interaction interface) was not dissected","Signaling pathways downstream of ZMYND12 loss were not explored"]},{"year":2024,"claim":"How ZMYND12 influences flagellar beating beyond structural assembly was unclear; knockout mice revealed that ZMYND12 interacts with PRKACA and is required for maintaining PRKACA levels in sperm, linking ZMYND12 to cAMP-dependent signaling during capacitation and explaining the motility defect.","evidence":"CRISPR/Cas9 knockout mouse model with sperm motility and capacitation assays, co-immunoprecipitation, mass spectrometry","pmids":["39066891"],"confidence":"High","gaps":["Whether ZMYND12 directly scaffolds PRKACA or stabilizes it indirectly is unresolved","Downstream PKA substrates affected in the absence of ZMYND12 have not been mapped","Whether the ZMYND12–PRKACA interaction is relevant in motile cilia beyond sperm flagella is unknown"]},{"year":null,"claim":"The structural basis for ZMYND12's integration into the IDA complex, the specific function of its MYND zinc-finger domain, and whether its role in PKA signaling extends to other motile-ciliated tissues remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural model of ZMYND12 within the IDA repeat","MYND domain binding partners or histone/protein substrates not identified","Role in airway or ependymal motile cilia not tested in mammalian models"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["Inner dynein arm (IDA) complex"],"partners":["TTC29","DNAH1","PRKACA","DNALI1","WDR66"],"other_free_text":[]},"mechanistic_narrative":"ZMYND12 is a structural subunit of the axonemal inner dynein arm (IDA) complex that forms a complex with TTC29, DNAH1, and PRKACA to support flagellar and ciliary assembly and motility [PMID:37934199, PMID:39066891]. Loss of ZMYND12 disrupts axonemal localization of IDA-associated proteins including DNAH1, DNALI1, WDR66, and TTC29 in human sperm, and ZMYND12 knockout mice exhibit reduced sperm motility, impaired capacitation, and decreased PRKACA levels, establishing a mechanistic link between ZMYND12 and cAMP-dependent signaling during sperm function [PMID:39066891, PMID:37934199]. Zebrafish crispants targeting zmynd12 recapitulate ciliary phenotypes, confirming a conserved role in cilia function beyond spermatogenesis [PMID:36533556]. Biallelic loss-of-function variants in ZMYND12 cause male infertility due to multiple morphological abnormalities of the sperm flagella [PMID:37934199]."},"prefetch_data":{"uniprot":{"accession":"Q9H0C1","full_name":"Zinc finger MYND domain-containing protein 12","aliases":[],"length_aa":365,"mass_kda":41.8,"function":"Required for sperm flagellum function and male fertility","subcellular_location":"Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q9H0C1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZMYND12","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZMYND12","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"fallopian tube","ntpm":16.1},{"tissue":"testis","ntpm":26.9}],"url":"https://www.proteinatlas.org/search/ZMYND12"},"hgnc":{"alias_symbol":["DKFZp434N2435"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0C1","domains":[{"cath_id":"-","chopping":"2-53","consensus_level":"medium","plddt":91.0167,"start":2,"end":53},{"cath_id":"1.25.40.10","chopping":"77-208","consensus_level":"medium","plddt":96.4142,"start":77,"end":208},{"cath_id":"1.25.40.10","chopping":"253-265_272-365","consensus_level":"medium","plddt":82.033,"start":253,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0C1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0C1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0C1-F1-predicted_aligned_error_v6.png","plddt_mean":90.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZMYND12","jax_strain_url":"https://www.jax.org/strain/search?query=ZMYND12"},"sequence":{"accession":"Q9H0C1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0C1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0C1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0C1"}},"corpus_meta":[{"pmid":"36533556","id":"PMC_36533556","title":"Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants.","date":"2022","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/36533556","citation_count":17,"is_preprint":false},{"pmid":"37934199","id":"PMC_37934199","title":"Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37934199","citation_count":13,"is_preprint":false},{"pmid":"35606283","id":"PMC_35606283","title":"A genome-wide association study on frequent exacerbation of asthma depending on smoking status.","date":"2022","source":"Respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35606283","citation_count":10,"is_preprint":false},{"pmid":"39066891","id":"PMC_39066891","title":"ZMYND12 serves as an IDAd subunit that is essential for sperm motility in mice.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/39066891","citation_count":3,"is_preprint":false},{"pmid":"42039311","id":"PMC_42039311","title":"Selection signatures on the autosomes and the X chromosome in the prolific Belclare sheep breed.","date":"2026","source":"Veterinary and animal science","url":"https://pubmed.ncbi.nlm.nih.gov/42039311","citation_count":0,"is_preprint":false},{"pmid":"40926514","id":"PMC_40926514","title":"Polystyrene Nanoparticles Induce Transcriptional Repression in TM4 Sertoli Cells.","date":"2025","source":"Journal of applied toxicology : JAT","url":"https://pubmed.ncbi.nlm.nih.gov/40926514","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4671,"output_tokens":903,"usd":0.013779},"stage2":{"model":"claude-opus-4-6","input_tokens":4089,"output_tokens":1546,"usd":0.088642},"total_usd":0.102421,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"ZMYND12 forms an axonemal complex with TTC29 and DNAH1, is required for flagellum function and assembly, and its localization to the axoneme was confirmed in the Trypanosoma brucei ortholog TbTAX-1; RNAi knockdown of TbTAX-1 dramatically impaired flagellar motility; in human patients with homozygous ZMYND12 variants, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29 in sperm cells.\",\n      \"method\": \"Co-immunoprecipitation, ultrastructure expansion microscopy, comparative proteomics (Trypanosoma and Ttc29 KO mice), RNAi knockdown, immunofluorescence in human sperm, whole-exome sequencing\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, proteomics, RNAi functional readout, expansion microscopy, human patient immunofluorescence) in a single study with rigorous controls\",\n      \"pmids\": [\"37934199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZMYND12 functions as a subunit of the inner dynein arm (IDA) complex in sperm flagella; it interacts with TTC29 and PRKACA, and ZMYND12 knockout mice exhibit reduced sperm motile velocity, impaired capacitation, and decreased PRKACA levels in sperm, indicating that ZMYND12 supports flagellar beating and capacitation through its association with PRKACA.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation, co-immunoprecipitation, mass spectrometry, sperm motility and capacitation assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vivo KO with defined phenotypic readout combined with Co-IP/MS identifying interacting partners and mechanistic link to PRKACA\",\n      \"pmids\": [\"39066891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ZMYND12 is a cilia-associated gene; CRISPR/Cas9 F0 crispant embryos targeting zmynd12 in zebrafish recapitulate ciliary phenotypes, placing ZMYND12 in the category of genes required for cilia function.\",\n      \"method\": \"Multiple-guide CRISPR/Cas9 F0 crispant zebrafish screen with ciliary phenotype readout\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with defined ciliary phenotypic readout, but limited mechanistic resolution beyond functional requirement\",\n      \"pmids\": [\"36533556\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND12 is an axonemal inner dynein arm (IDA) subunit that forms a complex with TTC29, DNAH1, and PRKACA to support flagellar/ciliary beating and assembly; loss of ZMYND12 disrupts localization of multiple IDA-associated proteins, impairs sperm motility and capacitation, and causes male infertility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZMYND12 is a structural subunit of the axonemal inner dynein arm (IDA) complex that forms a complex with TTC29, DNAH1, and PRKACA to support flagellar and ciliary assembly and motility [PMID:37934199, PMID:39066891]. Loss of ZMYND12 disrupts axonemal localization of IDA-associated proteins including DNAH1, DNALI1, WDR66, and TTC29 in human sperm, and ZMYND12 knockout mice exhibit reduced sperm motility, impaired capacitation, and decreased PRKACA levels, establishing a mechanistic link between ZMYND12 and cAMP-dependent signaling during sperm function [PMID:39066891, PMID:37934199]. Zebrafish crispants targeting zmynd12 recapitulate ciliary phenotypes, confirming a conserved role in cilia function beyond spermatogenesis [PMID:36533556]. Biallelic loss-of-function variants in ZMYND12 cause male infertility due to multiple morphological abnormalities of the sperm flagella [PMID:37934199].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Whether ZMYND12 is required for cilia function in vivo was unknown; zebrafish F0 crispants targeting zmynd12 displayed ciliary phenotypes, establishing ZMYND12 as a cilia-associated gene with a conserved functional requirement.\",\n      \"evidence\": \"Multiple-guide CRISPR/Cas9 F0 crispant screen in zebrafish with ciliary phenotype readout\",\n      \"pmids\": [\"36533556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mechanistic resolution beyond a general requirement for cilia function\",\n        \"Molecular partners and subciliary localization were not identified\",\n        \"F0 crispant mosaicism limits quantitative phenotypic interpretation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The molecular context of ZMYND12 within the axoneme was undefined; co-immunoprecipitation, proteomics, and expansion microscopy demonstrated that ZMYND12 forms a complex with TTC29 and DNAH1, localizes to the axoneme, and is required for proper localization of multiple IDA subunits (DNAH1, DNALI1, WDR66, TTC29), with RNAi knockdown of the Trypanosoma ortholog confirming a conserved role in flagellar motility.\",\n      \"evidence\": \"Co-IP, comparative proteomics (Trypanosoma and Ttc29 KO mice), RNAi knockdown in T. brucei, ultrastructure expansion microscopy, immunofluorescence in human patient sperm, whole-exome sequencing\",\n      \"pmids\": [\"37934199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural position of ZMYND12 within the IDA repeat was not resolved\",\n        \"The MYND zinc-finger domain's specific molecular function (e.g., protein–protein interaction interface) was not dissected\",\n        \"Signaling pathways downstream of ZMYND12 loss were not explored\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"How ZMYND12 influences flagellar beating beyond structural assembly was unclear; knockout mice revealed that ZMYND12 interacts with PRKACA and is required for maintaining PRKACA levels in sperm, linking ZMYND12 to cAMP-dependent signaling during capacitation and explaining the motility defect.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mouse model with sperm motility and capacitation assays, co-immunoprecipitation, mass spectrometry\",\n      \"pmids\": [\"39066891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ZMYND12 directly scaffolds PRKACA or stabilizes it indirectly is unresolved\",\n        \"Downstream PKA substrates affected in the absence of ZMYND12 have not been mapped\",\n        \"Whether the ZMYND12–PRKACA interaction is relevant in motile cilia beyond sperm flagella is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for ZMYND12's integration into the IDA complex, the specific function of its MYND zinc-finger domain, and whether its role in PKA signaling extends to other motile-ciliated tissues remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural model of ZMYND12 within the IDA repeat\",\n        \"MYND domain binding partners or histone/protein substrates not identified\",\n        \"Role in airway or ependymal motile cilia not tested in mammalian models\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"Inner dynein arm (IDA) complex\"\n    ],\n    \"partners\": [\n      \"TTC29\",\n      \"DNAH1\",\n      \"PRKACA\",\n      \"DNALI1\",\n      \"WDR66\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}