{"gene":"KCTD3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2013,"finding":"KCTD3 specifically binds to HCN3 (but not other HCN family members) via its C-terminal half, and this interaction profoundly up-regulates cell surface expression and current density of HCN3. The complete KCTD3 protein including the N-terminal tetramerization domain is required for current up-regulation, while the C-terminal half alone is sufficient for binding. The C-terminus of HCN3 is crucially required for the interaction; replacing the cytosolic C-terminus of HCN2 with the HCN3 C-terminus renders HCN2 sensitive to KCTD3 regulation. No evidence was found for channel complexes containing both TRIP8b and KCTD3.","method":"Co-immunoprecipitation, domain-deletion/swap mutagenesis, electrophysiology (current density measurements), cell surface expression assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including binding assays, domain mutagenesis, and functional electrophysiology in a single focused study","pmids":["23382386"],"is_preprint":false},{"year":2000,"finding":"NY-REN-45 (KCTD3) shares 55% amino acid identity with SB1 (SETA binding protein 1), a novel protein identified by yeast two-hybrid screening using the SH3 domain of SETA. In vitro confrontation and co-immunoprecipitation confirmed that SB1 (the NY-REN-45 paralog) binds to SETA; this established that the NY-REN-45/KCTD3 protein family members interact with the SH3 adaptor protein SETA.","method":"Yeast two-hybrid screening, in vitro confrontation assay, co-immunoprecipitation","journal":"Cellular signalling","confidence":"Low","confidence_rationale":"Tier 3 / Weak — the direct binding experiment was performed on the SB1 paralog (55% identity to NY-REN-45/KCTD3), not KCTD3 itself; single lab, single method for the family member","pmids":["11152963"],"is_preprint":false},{"year":2018,"finding":"Biallelic loss-of-function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy, global developmental delay, hypotonia, and posterior fossa abnormalities (cerebellar hypoplasia/Dandy-Walker malformation), establishing KCTD3 as required for normal brain and cerebellar development.","method":"Whole exome sequencing with segregation analysis in four consanguineous families (seven affected individuals)","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function genetics with clear phenotypic readout replicated across four independent families, but mechanistic pathway not defined","pmids":["29406573"],"is_preprint":false},{"year":2023,"finding":"A biallelic nonsense variant in KCTD3 (c.1192C>T; p.R398*) arising from paternal uniparental isodisomy of chromosome 1 causes developmental epileptic encephalopathy with brain structural abnormalities, confirming that complete loss of KCTD3 protein function is pathogenic.","method":"Whole exome sequencing, chromosomal microarray (UPD identification), family segregation analysis","journal":"Human genome variation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single case with genetic confirmation of biallelic loss-of-function, consistent with prior series but single patient","pmids":["37550298"],"is_preprint":false}],"current_model":"KCTD3 functions as an accessory subunit of native HCN3 channel complexes, specifically binding the C-terminus of HCN3 via its own C-terminal domain and requiring its N-terminal tetramerization domain to up-regulate HCN3 cell surface expression and current density; biallelic loss-of-function mutations in humans cause developmental epileptic encephalopathy with cerebellar abnormalities, consistent with its high expression in brain and kidney."},"narrative":{"mechanistic_narrative":"KCTD3 is an accessory subunit of native HCN3 channel complexes that governs the surface availability of this hyperpolarization-activated channel in the brain [PMID:23382386]. It binds selectively to HCN3 — and not to other HCN family members — through its C-terminal half, while its N-terminal tetramerization domain is additionally required to up-regulate HCN3 cell surface expression and current density; the cytosolic C-terminus of HCN3 confers this specificity, since transplanting it onto HCN2 renders HCN2 KCTD3-responsive [PMID:23382386]. Consistent with a role in neural function, biallelic loss-of-function mutations in KCTD3 cause developmental epileptic encephalopathy with global developmental delay, hypotonia, and posterior fossa/cerebellar abnormalities [PMID:29406573, PMID:37550298]. Beyond its regulation of HCN3 trafficking, no further biochemical mechanism connecting KCTD3 loss to the neurodevelopmental phenotype has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Establishing how KCTD3 acts on ion channels, this work showed it is a selective HCN3 accessory subunit that requires both a binding domain and an oligomerization domain to enhance channel surface expression.","evidence":"Co-immunoprecipitation, domain-deletion/swap mutagenesis, and electrophysiology in heterologous cells","pmids":["23382386"],"confidence":"High","gaps":["Stoichiometry and structure of the KCTD3-HCN3 complex not resolved","Whether KCTD3 acts via a ubiquitin/Cullin-adaptor mechanism on HCN3 not tested","Native neuronal HCN3 regulation by KCTD3 not demonstrated in vivo"]},{"year":2018,"claim":"Linking KCTD3 to human disease, recessive loss-of-function established the gene as required for normal brain and cerebellar development.","evidence":"Whole exome sequencing with segregation in four consanguineous families (seven affected individuals)","pmids":["29406573"],"confidence":"Medium","gaps":["Causal mechanism linking KCTD3 loss to encephalopathy not defined","Whether the phenotype reflects disrupted HCN3 regulation untested","No functional assay of the patient alleles"]},{"year":2023,"claim":"Reinforcing pathogenicity of complete protein loss, a biallelic nonsense variant arising via uniparental isodisomy reproduced the encephalopathy phenotype.","evidence":"Whole exome sequencing, chromosomal microarray for UPD, family segregation in a single case","pmids":["37550298"],"confidence":"Medium","gaps":["Single patient","No protein-level confirmation of loss","Mechanistic pathway from null allele to phenotype not addressed"]},{"year":null,"claim":"It remains unknown whether the neurodevelopmental phenotype of KCTD3 loss arises directly from dysregulated HCN3 channel trafficking or from a distinct, uncharacterized function.","evidence":"No timeline study connects the HCN3 regulatory mechanism to the disease phenotype","pmids":[],"confidence":"Low","gaps":["No animal model linking KCTD3 loss to HCN3 dysfunction","No structural basis for the KCTD3-HCN3 interaction","Possible additional substrates/partners not surveyed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2]}],"complexes":["HCN3 channel complex"],"partners":["HCN3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y597","full_name":"BTB/POZ domain-containing protein KCTD3","aliases":["Renal carcinoma antigen NY-REN-45"],"length_aa":815,"mass_kda":89.0,"function":"Accessory subunit of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) up-regulating its cell-surface expression and current density without affecting its voltage dependence and kinetics","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y597/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KCTD3","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":[{"gene":"SNX27","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/KCTD3","total_profiled":1310},"omim":[{"mim_id":"613272","title":"POTASSIUM CHANNEL TETRAMERIZATION DOMAIN-CONTAINING PROTEIN 3; KCTD3","url":"https://www.omim.org/entry/613272"},{"mim_id":"612100","title":"AUTISM, SUSCEPTIBILITY TO, 15; AUTS15","url":"https://www.omim.org/entry/612100"},{"mim_id":"609973","title":"HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED POTASSIUM CHANNEL 3; HCN3","url":"https://www.omim.org/entry/609973"},{"mim_id":"604569","title":"CONTACTIN-ASSOCIATED PROTEIN-LIKE 2; CNTNAP2","url":"https://www.omim.org/entry/604569"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KCTD3"},"hgnc":{"alias_symbol":["NY-REN-45"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y597","domains":[{"cath_id":"3.30.710.10","chopping":"18-115","consensus_level":"high","plddt":90.2321,"start":18,"end":115}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y597","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y597-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y597-F1-predicted_aligned_error_v6.png","plddt_mean":70.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KCTD3","jax_strain_url":"https://www.jax.org/strain/search?query=KCTD3"},"sequence":{"accession":"Q9Y597","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y597.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y597/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y597"}},"corpus_meta":[{"pmid":"25558065","id":"PMC_25558065","title":"Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/25558065","citation_count":381,"is_preprint":false},{"pmid":"19582487","id":"PMC_19582487","title":"Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder.","date":"2009","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19582487","citation_count":101,"is_preprint":false},{"pmid":"31197948","id":"PMC_31197948","title":"KCTD: A new gene family involved in neurodevelopmental and neuropsychiatric disorders.","date":"2019","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31197948","citation_count":100,"is_preprint":false},{"pmid":"11152963","id":"PMC_11152963","title":"SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins.","date":"2000","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/11152963","citation_count":56,"is_preprint":false},{"pmid":"32952011","id":"PMC_32952011","title":"Using imputed whole-genome sequence variants to uncover candidate mutations and genes affecting milking speed and temperament in Holstein cattle.","date":"2020","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/32952011","citation_count":29,"is_preprint":false},{"pmid":"23382386","id":"PMC_23382386","title":"Up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) by specific interaction with K+ channel tetramerization domain-containing protein 3 (KCTD3).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23382386","citation_count":20,"is_preprint":false},{"pmid":"29406573","id":"PMC_29406573","title":"Phenotypic characterization of KCTD3-related developmental epileptic encephalopathy.","date":"2018","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29406573","citation_count":18,"is_preprint":false},{"pmid":"28075205","id":"PMC_28075205","title":"A Genomic and Protein-Protein Interaction Analyses of Nonsyndromic Hearing Impairment in Cameroon Using Targeted Genomic Enrichment and Massively Parallel Sequencing.","date":"2017","source":"Omics : a journal of integrative biology","url":"https://pubmed.ncbi.nlm.nih.gov/28075205","citation_count":13,"is_preprint":false},{"pmid":"37469193","id":"PMC_37469193","title":"DNA methylation at birth and lateral ventricular volume in childhood: a neuroimaging epigenetics study.","date":"2023","source":"Journal of child psychology and psychiatry, and allied disciplines","url":"https://pubmed.ncbi.nlm.nih.gov/37469193","citation_count":6,"is_preprint":false},{"pmid":"40290421","id":"PMC_40290421","title":"Genetic aetiologies in relation to response to the ketogenic diet in 226 children with epilepsy.","date":"2025","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/40290421","citation_count":4,"is_preprint":false},{"pmid":"25353171","id":"PMC_25353171","title":"Genetic analysis of intracapillary glomerular lipoprotein deposits in aging mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25353171","citation_count":3,"is_preprint":false},{"pmid":"37550298","id":"PMC_37550298","title":"Biallelic KCTD3 nonsense variant derived from paternal uniparental isodisomy of chromosome 1 in a patient with developmental epileptic encephalopathy and distinctive features.","date":"2023","source":"Human genome variation","url":"https://pubmed.ncbi.nlm.nih.gov/37550298","citation_count":1,"is_preprint":false},{"pmid":"41158273","id":"PMC_41158273","title":"Establishment and characterization of two patient-derived cell lines from a patient with gallbladder carcinoma.","date":"2025","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/41158273","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9333,"output_tokens":1167,"usd":0.022752,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7707,"output_tokens":1517,"usd":0.03823,"stage2_stop_reason":"end_turn"},"total_usd":0.060982,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"KCTD3 specifically binds to HCN3 (but not other HCN family members) via its C-terminal half, and this interaction profoundly up-regulates cell surface expression and current density of HCN3. The complete KCTD3 protein including the N-terminal tetramerization domain is required for current up-regulation, while the C-terminal half alone is sufficient for binding. The C-terminus of HCN3 is crucially required for the interaction; replacing the cytosolic C-terminus of HCN2 with the HCN3 C-terminus renders HCN2 sensitive to KCTD3 regulation. No evidence was found for channel complexes containing both TRIP8b and KCTD3.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion/swap mutagenesis, electrophysiology (current density measurements), cell surface expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including binding assays, domain mutagenesis, and functional electrophysiology in a single focused study\",\n      \"pmids\": [\"23382386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NY-REN-45 (KCTD3) shares 55% amino acid identity with SB1 (SETA binding protein 1), a novel protein identified by yeast two-hybrid screening using the SH3 domain of SETA. In vitro confrontation and co-immunoprecipitation confirmed that SB1 (the NY-REN-45 paralog) binds to SETA; this established that the NY-REN-45/KCTD3 protein family members interact with the SH3 adaptor protein SETA.\",\n      \"method\": \"Yeast two-hybrid screening, in vitro confrontation assay, co-immunoprecipitation\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — the direct binding experiment was performed on the SB1 paralog (55% identity to NY-REN-45/KCTD3), not KCTD3 itself; single lab, single method for the family member\",\n      \"pmids\": [\"11152963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic loss-of-function mutations in KCTD3 lead to a consistent phenotype of developmental epileptic encephalopathy, global developmental delay, hypotonia, and posterior fossa abnormalities (cerebellar hypoplasia/Dandy-Walker malformation), establishing KCTD3 as required for normal brain and cerebellar development.\",\n      \"method\": \"Whole exome sequencing with segregation analysis in four consanguineous families (seven affected individuals)\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function genetics with clear phenotypic readout replicated across four independent families, but mechanistic pathway not defined\",\n      \"pmids\": [\"29406573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A biallelic nonsense variant in KCTD3 (c.1192C>T; p.R398*) arising from paternal uniparental isodisomy of chromosome 1 causes developmental epileptic encephalopathy with brain structural abnormalities, confirming that complete loss of KCTD3 protein function is pathogenic.\",\n      \"method\": \"Whole exome sequencing, chromosomal microarray (UPD identification), family segregation analysis\",\n      \"journal\": \"Human genome variation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single case with genetic confirmation of biallelic loss-of-function, consistent with prior series but single patient\",\n      \"pmids\": [\"37550298\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KCTD3 functions as an accessory subunit of native HCN3 channel complexes, specifically binding the C-terminus of HCN3 via its own C-terminal domain and requiring its N-terminal tetramerization domain to up-regulate HCN3 cell surface expression and current density; biallelic loss-of-function mutations in humans cause developmental epileptic encephalopathy with cerebellar abnormalities, consistent with its high expression in brain and kidney.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KCTD3 is an accessory subunit of native HCN3 channel complexes that governs the surface availability of this hyperpolarization-activated channel in the brain [#0]. It binds selectively to HCN3 — and not to other HCN family members — through its C-terminal half, while its N-terminal tetramerization domain is additionally required to up-regulate HCN3 cell surface expression and current density; the cytosolic C-terminus of HCN3 confers this specificity, since transplanting it onto HCN2 renders HCN2 KCTD3-responsive [#0]. Consistent with a role in neural function, biallelic loss-of-function mutations in KCTD3 cause developmental epileptic encephalopathy with global developmental delay, hypotonia, and posterior fossa/cerebellar abnormalities [#2, #3]. Beyond its regulation of HCN3 trafficking, no further biochemical mechanism connecting KCTD3 loss to the neurodevelopmental phenotype has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing how KCTD3 acts on ion channels, this work showed it is a selective HCN3 accessory subunit that requires both a binding domain and an oligomerization domain to enhance channel surface expression.\",\n      \"evidence\": \"Co-immunoprecipitation, domain-deletion/swap mutagenesis, and electrophysiology in heterologous cells\",\n      \"pmids\": [\"23382386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the KCTD3-HCN3 complex not resolved\", \"Whether KCTD3 acts via a ubiquitin/Cullin-adaptor mechanism on HCN3 not tested\", \"Native neuronal HCN3 regulation by KCTD3 not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking KCTD3 to human disease, recessive loss-of-function established the gene as required for normal brain and cerebellar development.\",\n      \"evidence\": \"Whole exome sequencing with segregation in four consanguineous families (seven affected individuals)\",\n      \"pmids\": [\"29406573\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking KCTD3 loss to encephalopathy not defined\", \"Whether the phenotype reflects disrupted HCN3 regulation untested\", \"No functional assay of the patient alleles\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reinforcing pathogenicity of complete protein loss, a biallelic nonsense variant arising via uniparental isodisomy reproduced the encephalopathy phenotype.\",\n      \"evidence\": \"Whole exome sequencing, chromosomal microarray for UPD, family segregation in a single case\",\n      \"pmids\": [\"37550298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient\", \"No protein-level confirmation of loss\", \"Mechanistic pathway from null allele to phenotype not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the neurodevelopmental phenotype of KCTD3 loss arises directly from dysregulated HCN3 channel trafficking or from a distinct, uncharacterized function.\",\n      \"evidence\": \"No timeline study connects the HCN3 regulatory mechanism to the disease phenotype\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No animal model linking KCTD3 loss to HCN3 dysfunction\", \"No structural basis for the KCTD3-HCN3 interaction\", \"Possible additional substrates/partners not surveyed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"HCN3 channel complex\"],\n    \"partners\": [\"HCN3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}