{"gene":"ZMYND12","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2023,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, patient immunofluorescence, RNAi functional validation, and comparative proteomics across two model systems in a single study","pmids":["37934199"],"is_preprint":false},{"year":2024,"finding":"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.","method":"CRISPR/Cas9 knockout mouse generation; fertility and motility assays; co-immunoprecipitation combined with mass spectrometry; western blot for PRKACA levels","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular phenotype, co-IP/MS identifying binding partners, and downstream mechanistic readout (PRKACA reduction) in a single rigorous study","pmids":["39066891"],"is_preprint":false},{"year":2022,"finding":"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.","method":"CRISPR/Cas9 F0 crispant zebrafish; ciliary phenotype analysis","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function with defined ciliary phenotype in a well-validated crispant system, but single study and phenotype described only briefly within a broader multi-gene screen","pmids":["36533556"],"is_preprint":false}],"current_model":"ZMYND12 is an axonemal inner dynein arm (IDA) subunit that forms a complex with TTC29 and DNAH1; loss of ZMYND12 disrupts proper localization of IDA components (DNAH1, DNALI1, WDR66, TTC29), reduces PRKACA levels in sperm, and impairs flagellar beating, capacitation, and male fertility in humans, mice, and Trypanosoma, while zebrafish crispants also display ciliary phenotypes."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2022,"claim":"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","pmids":["36533556"],"confidence":"Medium","gaps":["Phenotype described only briefly within a broader multi-gene screen","No molecular interactors or axonemal placement defined","Does not address the sperm flagellum specifically"]},{"year":2023,"claim":"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","pmids":["37934199"],"confidence":"High","gaps":["Stoichiometry and structural arrangement of the ZMYND12–TTC29–DNAH1 complex not resolved","Mechanism by which ZMYND12 directs DNAH1/DNALI1/WDR66 localization not defined"]},{"year":2024,"claim":"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","pmids":["39066891"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"How ZMYND12 mechanistically templates IDA assembly and stabilizes PRKACA within the flagellar axoneme remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["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":{"molecular_activity":[],"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-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["axonemal inner dynein arm","ZMYND12–TTC29–DNAH1 axonemal complex"],"partners":["TTC29","DNAH1","PRKACA"],"other_free_text":[]}},"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":14,"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":"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},{"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5436,"output_tokens":1045,"usd":0.015991,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7552,"output_tokens":1717,"usd":0.040343,"stage2_stop_reason":"end_turn"},"total_usd":0.056334,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, patient immunofluorescence, RNAi functional validation, and comparative proteomics across two model systems in a single study\",\n      \"pmids\": [\"37934199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 knockout mouse generation; fertility and motility assays; co-immunoprecipitation combined with mass spectrometry; western blot for PRKACA levels\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular phenotype, co-IP/MS identifying binding partners, and downstream mechanistic readout (PRKACA reduction) in a single rigorous study\",\n      \"pmids\": [\"39066891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 F0 crispant zebrafish; ciliary phenotype analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function with defined ciliary phenotype in a well-validated crispant system, but single study and phenotype described only briefly within a broader multi-gene screen\",\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 and DNAH1; loss of ZMYND12 disrupts proper localization of IDA components (DNAH1, DNALI1, WDR66, TTC29), reduces PRKACA levels in sperm, and impairs flagellar beating, capacitation, and male fertility in humans, mice, and Trypanosoma, while zebrafish crispants also display ciliary phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZMYND12 is an axonemal inner dynein arm (IDA) subunit required for flagellar and ciliary motility and male fertility [#0, #1]. 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 [#0]. 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 [#1]. Loss of zmynd12 in zebrafish produces ciliary phenotypes, indicating a broader role in cilia-associated biology beyond the sperm flagellum [#2]. Homozygous ZMYND12 variants cause human male infertility [#0].\",\n  \"teleology\": [\n    {\n      \"year\": 2022,\n      \"claim\": \"Before any direct functional characterization, it was unknown whether ZMYND12 acted in motile cilia; in vivo loss-of-function established a ciliary requirement.\",\n      \"evidence\": \"CRISPR/Cas9 F0 crispant zebrafish with ciliary phenotype analysis\",\n      \"pmids\": [\n        \"36533556\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Phenotype described only briefly within a broader multi-gene screen\",\n        \"No molecular interactors or axonemal placement defined\",\n        \"Does not address the sperm flagellum specifically\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\n        \"37934199\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structural arrangement of the ZMYND12–TTC29–DNAH1 complex not resolved\",\n        \"Mechanism by which ZMYND12 directs DNAH1/DNALI1/WDR66 localization not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR/Cas9 knockout mice with fertility/motility assays, Co-IP/MS partner identification, and western blot for PRKACA\",\n      \"pmids\": [\n        \"39066891\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking ZMYND12 to PRKACA stability not established\",\n        \"Direct versus indirect nature of the ZMYND12–PRKACA interaction unresolved\",\n        \"Whether the capacitation defect is separable from the motility defect is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZMYND12 mechanistically templates IDA assembly and stabilizes PRKACA within the flagellar axoneme remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the ZMYND12–TTC29–DNAH1 complex\",\n        \"Biochemical basis for PRKACA abundance control unknown\",\n        \"No molecular activity assigned to ZMYND12 itself\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005929\",\n        \"supporting_discovery_ids\": [\n          0,\n          1,\n          2\n        ]\n      },\n      {\n        \"term_id\": \"GO:0005856\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-1474165\",\n        \"supporting_discovery_ids\": [\n          0,\n          1\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"axonemal inner dynein arm\",\n      \"ZMYND12–TTC29–DNAH1 axonemal complex\"\n    ],\n    \"partners\": [\n      \"TTC29\",\n      \"DNAH1\",\n      \"PRKACA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}