{"gene":"CCNQ","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2013,"finding":"CDK10 is a cyclin-dependent kinase activated by Cyclin M (product of FAM58A/CCNQ). The CDK10/CyclinM complex phosphorylates ETS2 in vitro, and in cells it positively controls ETS2 degradation by the proteasome. STAR syndrome-associated CyclinM mutants are unable to interact with CDK10. CyclinM silencing phenocopies CDK10 silencing in increasing c-Raf and conferring tamoxifen resistance.","method":"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, proteasome inhibition, cell-based assays with patient-derived cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with substrate phosphorylation, co-IP for complex formation, multiple orthogonal methods (knockdown, patient cells, proteasome inhibition), single rigorous study","pmids":["24218572"],"is_preprint":false},{"year":2016,"finding":"CDK10/CyclinM regulates actin network organization and suppresses ciliogenesis. In an unbiased screen, PKN2 (RhoA-associated kinase) was identified as a CDK10/CyclinM phosphorylation substrate; CDK10/CyclinM binds and phosphorylates PKN2 on threonines 121 and 124 within PKN2's RhoA-binding domain. Deficiency of CDK10/CyclinM or PKN2, or expression of non-phosphorylatable PKN2, destabilizes RhoA protein and the actin network, promoting cilia assembly and elongation. Ectopic RhoA expression overrides ciliogenesis induced by CDK10/CyclinM knockdown.","method":"siRNA knockdown, in vitro kinase assay with phospho-mapping, Co-immunoprecipitation, overexpression rescue, immunofluorescence of primary cilia, unbiased phosphorylation substrate screen, kidney sections from STAR patient","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with site-specific mutagenesis, substrate identification screen, epistasis rescue experiment, multiple orthogonal methods in one study","pmids":["27104747"],"is_preprint":false},{"year":2020,"finding":"An optimized peptide phosphorylation substrate for CDK10/CyclinM was identified, and a homogeneous miniaturized in vitro kinase assay was developed. Known CDK inhibitors (SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573, AT7519) and NVP-2 (a CDK9 inhibitor) potently inhibit CDK10/CyclinM in vitro.","method":"In vitro kinase assay, peptide substrate optimization, inhibitor profiling","journal":"Frontiers in chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with substrate identification and inhibitor profiling, single lab, biochemical characterization","pmids":["32175313"],"is_preprint":false},{"year":2021,"finding":"Truncated variants of CDK10 and CyclinM (from STAR/Al Kaissi syndrome patients) retain ability to form a CDK10/CyclinM heterodimer. The CyclinM truncated variant partially activates CDK10 kinase activity in vitro, whereas the CDK10 truncated variant remains inactive. In human cells, the CDK10 variant is strongly degraded by the proteasome and the CyclinM variant is partially degraded, resulting in total loss of CDK10/CyclinM activity in the Al Kaissi patient.","method":"Structural modeling, baculovirus expression in insect cells with in vitro kinase assay, yeast two-hybrid, proteasome inhibition in human cells","journal":"Molecular genetics & genomic medicine","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, two-hybrid, cell-based proteasome experiments; multiple methods, single lab","pmids":["34369103"],"is_preprint":false},{"year":2017,"finding":"A homozygous loss-of-function frameshift mutation in CDK10 (c.870_871del, p.Trp291Alafs*18) in a patient leads to fewer and shorter primary cilia upon starvation, confirming CDK10 is required for normal ciliogenesis. Patient cells also appeared less elongated and more densely populated, suggesting CDK10 affects the cytoskeleton.","method":"Exome sequencing, immunofluorescence staining of cilia (acetylated-tubulin, γ-tubulin, Arl13b) in patient-derived cells","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cell phenotyping with direct cilia staining, functional consequence of loss-of-function mutation, corroborates prior mechanistic findings","pmids":["29130579"],"is_preprint":false},{"year":2022,"finding":"A novel tail-extension frameshift variant in CCNQ (c.502_518delinsA) impairs cyclin M expression but increases the binding affinity of the CDK10-cyclin M complex, a distinct mechanism from previously described loss-of-function mutations. Functional effects were validated in cultured cells and zebrafish embryos.","method":"Whole-exome sequencing, Sanger sequencing validation, cell transfection with mutant construct, zebrafish embryo transfection","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, binding affinity claim not fully elaborated methodologically","pmids":["36284407"],"is_preprint":false}],"current_model":"CCNQ (CyclinM/FAM58A) encodes an activating cyclin that forms a heterodimeric protein kinase complex with CDK10; this CDK10/CyclinM complex phosphorylates ETS2 (promoting its proteasomal degradation and suppressing MAPK/c-Raf signaling) and phosphorylates PKN2 on Thr121/124 within its RhoA-binding domain, thereby stabilizing RhoA and the actin network to suppress primary cilia assembly and elongation; loss-of-function mutations in either subunit cause the developmental ciliopathy STAR syndrome."},"narrative":{"mechanistic_narrative":"CCNQ (Cyclin M, FAM58A) encodes an activating cyclin that binds and activates the cyclin-dependent kinase CDK10 to form a heterodimeric protein kinase that governs cell signaling and primary cilium homeostasis [PMID:24218572, PMID:27104747]. The CDK10/CyclinM complex phosphorylates ETS2 in vitro and drives its proteasomal degradation in cells; loss of CyclinM phenocopies loss of CDK10 by elevating c-Raf and conferring tamoxifen resistance [PMID:24218572]. The complex also phosphorylates PKN2 on threonines 121 and 124 within its RhoA-binding domain, and loss of CDK10/CyclinM (or expression of non-phosphorylatable PKN2) destabilizes RhoA and the actin network, thereby promoting primary cilia assembly and elongation; ectopic RhoA reverses the ciliogenesis induced by complex knockdown [PMID:27104747]. STAR/Al Kaissi syndrome-associated CyclinM variants disrupt this complex: classical mutants fail to interact with CDK10, while truncated variants retain heterodimer formation but yield loss of complex kinase activity through proteasomal degradation [PMID:24218572, PMID:34369103]. The kinase is biochemically tractable and is potently inhibited in vitro by several known CDK inhibitors [PMID:32175313].","teleology":[{"year":2013,"claim":"Established that CCNQ functions as the activating cyclin partner of CDK10 and that the resulting kinase controls ETS2 stability and MAPK signaling, answering what molecular activity CCNQ confers and how its disease mutations act.","evidence":"Co-immunoprecipitation, in vitro kinase assay on ETS2, siRNA knockdown, proteasome inhibition, and patient-derived cells","pmids":["24218572"],"confidence":"High","gaps":["Did not address cytoskeletal or ciliary roles","ETS2 phosphosites and the in vivo signaling consequences in development not mapped"]},{"year":2016,"claim":"Identified PKN2 as a CDK10/CyclinM substrate and defined the RhoA-actin axis through which the complex suppresses ciliogenesis, connecting the kinase to a cytoskeletal and ciliary phenotype relevant to STAR syndrome.","evidence":"Unbiased phospho-substrate screen, in vitro kinase assay with site-directed phospho-mapping (Thr121/124), siRNA knockdown, RhoA overexpression rescue, cilia immunofluorescence, and STAR patient kidney sections","pmids":["27104747"],"confidence":"High","gaps":["Mechanism by which PKN2 phosphorylation stabilizes RhoA not resolved at molecular level","Tissue-specific contribution of cilia defect to STAR phenotype not established"]},{"year":2017,"claim":"Confirmed independently that loss of CDK10 kinase function impairs ciliogenesis in patient cells, corroborating the CCNQ/CDK10 complex's role in cilium formation.","evidence":"Exome sequencing and cilia immunofluorescence (acetylated-tubulin, γ-tubulin, Arl13b) in patient-derived cells","pmids":["29130579"],"confidence":"Medium","gaps":["Addresses CDK10 rather than CCNQ directly","Cytoskeletal phenotype described only qualitatively"]},{"year":2020,"claim":"Provided a tractable biochemical assay and demonstrated pharmacological inhibitability of the CDK10/CyclinM kinase, enabling future inhibitor and substrate studies.","evidence":"Optimized peptide substrate, miniaturized in vitro kinase assay, and profiling of known CDK inhibitors","pmids":["32175313"],"confidence":"Medium","gaps":["Inhibitors are not selective for CDK10/CyclinM","No cellular validation of inhibition"]},{"year":2021,"claim":"Resolved how STAR/Al Kaissi truncating variants impair the complex, showing heterodimer formation is retained but kinase activity is lost via proteasomal degradation of the subunits.","evidence":"Structural modeling, baculovirus expression with in vitro kinase assay, yeast two-hybrid, and proteasome inhibition in human cells","pmids":["34369103"],"confidence":"Medium","gaps":["Degradation pathway / E3 ligase not identified","In vivo developmental consequence not modeled"]},{"year":2022,"claim":"Reported an atypical CCNQ tail-extension variant that reduces cyclin M expression yet increases CDK10-cyclin M binding affinity, indicating disease alleles can act through mechanisms distinct from simple loss of interaction.","evidence":"Whole-exome and Sanger sequencing, mutant construct transfection in cultured cells, and zebrafish embryo transfection","pmids":["36284407"],"confidence":"Low","gaps":["Binding-affinity claim not methodologically elaborated","Functional consequence on kinase activity and ciliogenesis not directly measured","Single lab, not independently confirmed"]},{"year":null,"claim":"How CDK10/CyclinM substrate phosphorylation is integrated to control development across tissues, and whether ETS2 and PKN2 axes act independently or convergently in STAR syndrome pathogenesis, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo model linking specific substrate phosphorylation to organ malformation","Full substrate repertoire of the kinase unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,4]}],"complexes":["CDK10/CyclinM kinase"],"partners":["CDK10","ETS2","PKN2","RHOA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N1B3","full_name":"Cyclin-Q","aliases":["CDK10-activating cyclin","Cyclin-M","Cyclin-related protein FAM58A"],"length_aa":248,"mass_kda":28.4,"function":"Activating cyclin for the cyclin-associated kinase CDK10","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8N1B3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCNQ","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":74,"dependency_fraction":0.06756756756756757},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCNQ","total_profiled":1310},"omim":[{"mim_id":"300708","title":"CYCLIN Q; CCNQ","url":"https://www.omim.org/entry/300708"},{"mim_id":"300707","title":"TOE SYNDACTYLY, TELECANTHUS, AND ANOGENITAL AND RENAL MALFORMATIONS; STAR","url":"https://www.omim.org/entry/300707"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCNQ"},"hgnc":{"alias_symbol":["CycM"],"prev_symbol":["FAM58A"]},"alphafold":{"accession":"Q8N1B3","domains":[{"cath_id":"1.10.472.10","chopping":"21-131","consensus_level":"high","plddt":94.4341,"start":21,"end":131},{"cath_id":"1.10.472.10","chopping":"140-245","consensus_level":"high","plddt":90.5094,"start":140,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1B3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1B3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N1B3-F1-predicted_aligned_error_v6.png","plddt_mean":87.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCNQ","jax_strain_url":"https://www.jax.org/strain/search?query=CCNQ"},"sequence":{"accession":"Q8N1B3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N1B3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N1B3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N1B3"}},"corpus_meta":[{"pmid":"33446504","id":"PMC_33446504","title":"Prior 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japonicum cycM gene encodes a membrane-anchored homolog of mitochondrial cytochrome c.","date":"1991","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1657867","citation_count":60,"is_preprint":false},{"pmid":"9889979","id":"PMC_9889979","title":"Genes involved in the formation and assembly of rhizobial cytochromes and their role in symbiotic nitrogen fixation.","date":"1998","source":"Advances in microbial physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9889979","citation_count":52,"is_preprint":false},{"pmid":"10216157","id":"PMC_10216157","title":"Heterologous expression of soluble fragments of cytochrome c552 acting as electron donor to the Paracoccus denitrificans cytochrome c oxidase.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10216157","citation_count":46,"is_preprint":false},{"pmid":"7628479","id":"PMC_7628479","title":"Purification of Paracoccus denitrificans cytochrome c552 and sequence analysis of the gene.","date":"1995","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7628479","citation_count":46,"is_preprint":false},{"pmid":"11208782","id":"PMC_11208782","title":"Enhanced symbiotic performance by Rhizobium tropici glycogen synthase mutants.","date":"2001","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/11208782","citation_count":39,"is_preprint":false},{"pmid":"19450714","id":"PMC_19450714","title":"Identification of key DNA elements involved in promoter recognition by Mxr1p, a master regulator of methanol utilization pathway in Pichia pastoris.","date":"2009","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/19450714","citation_count":39,"is_preprint":false},{"pmid":"27104747","id":"PMC_27104747","title":"STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis.","date":"2016","source":"Cell cycle (Georgetown, 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/20583181","citation_count":7,"is_preprint":false},{"pmid":"36062518","id":"PMC_36062518","title":"Clinical and genetic approach in the characterization of newborns with anorectal malformation.","date":"2020","source":"The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians","url":"https://pubmed.ncbi.nlm.nih.gov/36062518","citation_count":6,"is_preprint":false},{"pmid":"34369103","id":"PMC_34369103","title":"Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34369103","citation_count":5,"is_preprint":false},{"pmid":"37967237","id":"PMC_37967237","title":"Copy number variants landscape of multiple cancers and clinical applications based on NGS gene panel.","date":"2023","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37967237","citation_count":5,"is_preprint":false},{"pmid":"25470021","id":"PMC_25470021","title":"Identification of sumoylated proteins in the silkworm Bombyx mori.","date":"2014","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25470021","citation_count":3,"is_preprint":false},{"pmid":"36284407","id":"PMC_36284407","title":"The identification of a novel CCNQ gene tail extension variant contributing to syndactyly, telecanthus and anogenital and renal malformations syndrome.","date":"2022","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36284407","citation_count":1,"is_preprint":false},{"pmid":"41096831","id":"PMC_41096831","title":"Candidate Transcript Panel in Semen Extracellular Vesicles Can Improve Prediction of Aggressiveness of Prostate Cancer.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41096831","citation_count":0,"is_preprint":false},{"pmid":"39887729","id":"PMC_39887729","title":"Toe Polydactyly and Supernumerary Nipple: Broadening the Phenotypic Spectrum of STAR Syndrome.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39887729","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14001,"output_tokens":1823,"usd":0.034674,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8701,"output_tokens":2377,"usd":0.051465,"stage2_stop_reason":"end_turn"},"total_usd":0.086139,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"CDK10 is a cyclin-dependent kinase activated by Cyclin M (product of FAM58A/CCNQ). The CDK10/CyclinM complex phosphorylates ETS2 in vitro, and in cells it positively controls ETS2 degradation by the proteasome. STAR syndrome-associated CyclinM mutants are unable to interact with CDK10. CyclinM silencing phenocopies CDK10 silencing in increasing c-Raf and conferring tamoxifen resistance.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, proteasome inhibition, cell-based assays with patient-derived cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with substrate phosphorylation, co-IP for complex formation, multiple orthogonal methods (knockdown, patient cells, proteasome inhibition), single rigorous study\",\n      \"pmids\": [\"24218572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDK10/CyclinM regulates actin network organization and suppresses ciliogenesis. In an unbiased screen, PKN2 (RhoA-associated kinase) was identified as a CDK10/CyclinM phosphorylation substrate; CDK10/CyclinM binds and phosphorylates PKN2 on threonines 121 and 124 within PKN2's RhoA-binding domain. Deficiency of CDK10/CyclinM or PKN2, or expression of non-phosphorylatable PKN2, destabilizes RhoA protein and the actin network, promoting cilia assembly and elongation. Ectopic RhoA expression overrides ciliogenesis induced by CDK10/CyclinM knockdown.\",\n      \"method\": \"siRNA knockdown, in vitro kinase assay with phospho-mapping, Co-immunoprecipitation, overexpression rescue, immunofluorescence of primary cilia, unbiased phosphorylation substrate screen, kidney sections from STAR patient\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with site-specific mutagenesis, substrate identification screen, epistasis rescue experiment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"27104747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"An optimized peptide phosphorylation substrate for CDK10/CyclinM was identified, and a homogeneous miniaturized in vitro kinase assay was developed. Known CDK inhibitors (SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573, AT7519) and NVP-2 (a CDK9 inhibitor) potently inhibit CDK10/CyclinM in vitro.\",\n      \"method\": \"In vitro kinase assay, peptide substrate optimization, inhibitor profiling\",\n      \"journal\": \"Frontiers in chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with substrate identification and inhibitor profiling, single lab, biochemical characterization\",\n      \"pmids\": [\"32175313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Truncated variants of CDK10 and CyclinM (from STAR/Al Kaissi syndrome patients) retain ability to form a CDK10/CyclinM heterodimer. The CyclinM truncated variant partially activates CDK10 kinase activity in vitro, whereas the CDK10 truncated variant remains inactive. In human cells, the CDK10 variant is strongly degraded by the proteasome and the CyclinM variant is partially degraded, resulting in total loss of CDK10/CyclinM activity in the Al Kaissi patient.\",\n      \"method\": \"Structural modeling, baculovirus expression in insect cells with in vitro kinase assay, yeast two-hybrid, proteasome inhibition in human cells\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, two-hybrid, cell-based proteasome experiments; multiple methods, single lab\",\n      \"pmids\": [\"34369103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous loss-of-function frameshift mutation in CDK10 (c.870_871del, p.Trp291Alafs*18) in a patient leads to fewer and shorter primary cilia upon starvation, confirming CDK10 is required for normal ciliogenesis. Patient cells also appeared less elongated and more densely populated, suggesting CDK10 affects the cytoskeleton.\",\n      \"method\": \"Exome sequencing, immunofluorescence staining of cilia (acetylated-tubulin, γ-tubulin, Arl13b) in patient-derived cells\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cell phenotyping with direct cilia staining, functional consequence of loss-of-function mutation, corroborates prior mechanistic findings\",\n      \"pmids\": [\"29130579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel tail-extension frameshift variant in CCNQ (c.502_518delinsA) impairs cyclin M expression but increases the binding affinity of the CDK10-cyclin M complex, a distinct mechanism from previously described loss-of-function mutations. Functional effects were validated in cultured cells and zebrafish embryos.\",\n      \"method\": \"Whole-exome sequencing, Sanger sequencing validation, cell transfection with mutant construct, zebrafish embryo transfection\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic detail in abstract, binding affinity claim not fully elaborated methodologically\",\n      \"pmids\": [\"36284407\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCNQ (CyclinM/FAM58A) encodes an activating cyclin that forms a heterodimeric protein kinase complex with CDK10; this CDK10/CyclinM complex phosphorylates ETS2 (promoting its proteasomal degradation and suppressing MAPK/c-Raf signaling) and phosphorylates PKN2 on Thr121/124 within its RhoA-binding domain, thereby stabilizing RhoA and the actin network to suppress primary cilia assembly and elongation; loss-of-function mutations in either subunit cause the developmental ciliopathy STAR syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCNQ (Cyclin M, FAM58A) encodes an activating cyclin that binds and activates the cyclin-dependent kinase CDK10 to form a heterodimeric protein kinase that governs cell signaling and primary cilium homeostasis [#0, #1]. The CDK10/CyclinM complex phosphorylates ETS2 in vitro and drives its proteasomal degradation in cells; loss of CyclinM phenocopies loss of CDK10 by elevating c-Raf and conferring tamoxifen resistance [#0]. The complex also phosphorylates PKN2 on threonines 121 and 124 within its RhoA-binding domain, and loss of CDK10/CyclinM (or expression of non-phosphorylatable PKN2) destabilizes RhoA and the actin network, thereby promoting primary cilia assembly and elongation; ectopic RhoA reverses the ciliogenesis induced by complex knockdown [#1]. STAR/Al Kaissi syndrome-associated CyclinM variants disrupt this complex: classical mutants fail to interact with CDK10, while truncated variants retain heterodimer formation but yield loss of complex kinase activity through proteasomal degradation [#0, #3]. The kinase is biochemically tractable and is potently inhibited in vitro by several known CDK inhibitors [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that CCNQ functions as the activating cyclin partner of CDK10 and that the resulting kinase controls ETS2 stability and MAPK signaling, answering what molecular activity CCNQ confers and how its disease mutations act.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro kinase assay on ETS2, siRNA knockdown, proteasome inhibition, and patient-derived cells\",\n      \"pmids\": [\"24218572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address cytoskeletal or ciliary roles\", \"ETS2 phosphosites and the in vivo signaling consequences in development not mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PKN2 as a CDK10/CyclinM substrate and defined the RhoA-actin axis through which the complex suppresses ciliogenesis, connecting the kinase to a cytoskeletal and ciliary phenotype relevant to STAR syndrome.\",\n      \"evidence\": \"Unbiased phospho-substrate screen, in vitro kinase assay with site-directed phospho-mapping (Thr121/124), siRNA knockdown, RhoA overexpression rescue, cilia immunofluorescence, and STAR patient kidney sections\",\n      \"pmids\": [\"27104747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PKN2 phosphorylation stabilizes RhoA not resolved at molecular level\", \"Tissue-specific contribution of cilia defect to STAR phenotype not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed independently that loss of CDK10 kinase function impairs ciliogenesis in patient cells, corroborating the CCNQ/CDK10 complex's role in cilium formation.\",\n      \"evidence\": \"Exome sequencing and cilia immunofluorescence (acetylated-tubulin, \\u03b3-tubulin, Arl13b) in patient-derived cells\",\n      \"pmids\": [\"29130579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Addresses CDK10 rather than CCNQ directly\", \"Cytoskeletal phenotype described only qualitatively\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided a tractable biochemical assay and demonstrated pharmacological inhibitability of the CDK10/CyclinM kinase, enabling future inhibitor and substrate studies.\",\n      \"evidence\": \"Optimized peptide substrate, miniaturized in vitro kinase assay, and profiling of known CDK inhibitors\",\n      \"pmids\": [\"32175313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Inhibitors are not selective for CDK10/CyclinM\", \"No cellular validation of inhibition\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how STAR/Al Kaissi truncating variants impair the complex, showing heterodimer formation is retained but kinase activity is lost via proteasomal degradation of the subunits.\",\n      \"evidence\": \"Structural modeling, baculovirus expression with in vitro kinase assay, yeast two-hybrid, and proteasome inhibition in human cells\",\n      \"pmids\": [\"34369103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation pathway / E3 ligase not identified\", \"In vivo developmental consequence not modeled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reported an atypical CCNQ tail-extension variant that reduces cyclin M expression yet increases CDK10-cyclin M binding affinity, indicating disease alleles can act through mechanisms distinct from simple loss of interaction.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing, mutant construct transfection in cultured cells, and zebrafish embryo transfection\",\n      \"pmids\": [\"36284407\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Binding-affinity claim not methodologically elaborated\", \"Functional consequence on kinase activity and ciliogenesis not directly measured\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDK10/CyclinM substrate phosphorylation is integrated to control development across tissues, and whether ETS2 and PKN2 axes act independently or convergently in STAR syndrome pathogenesis, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo model linking specific substrate phosphorylation to organ malformation\", \"Full substrate repertoire of the kinase unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"CDK10/CyclinM kinase\"],\n    \"partners\": [\"CDK10\", \"ETS2\", \"PKN2\", \"RHOA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":5,"faith_pct":100.0}}