{"gene":"PKD1L1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"Pkd1l1 physically interacts with Pkd2 (co-immunoprecipitation), co-localises with Pkd2 in the cilium of mouse node cells, and both proteins act downstream of nodal flow to establish left-right asymmetry; loss of Pkd1l1 phenocopies loss of Pkd2, with failure to activate asymmetric gene expression at the node and in the lateral plate mesoderm, and right isomerism of the lungs, despite normal node/cilia morphology and motility.","method":"Biochemical co-immunoprecipitation, cell biological co-localisation in cilia, phenotypic comparison of Pkd1l1 and Pkd2 point mutants (mouse genetics)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical interaction plus ciliary co-localisation plus genetic epistasis via matched mutant phenocopying, replicated across two independent labs in the same issue","pmids":["21307093"],"is_preprint":false},{"year":2011,"finding":"In medaka (zebrafish-related model), pkd1l1 is expressed exclusively in Kupffer's vesicle (KV); Pkd1l1 and Pkd2 interact and interdependently co-localise at motile KV cilia; all KV cilia contain Pkd1l1, Pkd2, and left-right dynein and are motile, indicating Pkd1l1-Pkd2 complexes function as the nodal flow sensor within motile cilia rather than in a separate immotile sensory population.","method":"Genetic mapping of medaka left-right mutant abecobe (abc) to pkd1l1; immunofluorescence co-localisation; interaction assay; ciliary motility analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning plus protein interaction plus co-localisation, independently replicating the mouse findings from the companion paper","pmids":["21307098"],"is_preprint":false},{"year":2010,"finding":"Pkd1l1-knockout mice develop situs inversus without hydrocephalus, sinusitis, or male infertility, indicating that Pkd1l1 loss causes laterality defects through dysfunction of mechanosensory (immotile) cilia rather than motile cilia, consistent with a sensory role analogous to Pkd1 in renal primary cilia.","method":"Constitutive Pkd1l1 knockout mouse; phenotype battery screening; comparative pathology with Dpcd/Poll and Nme7 knockouts that have motile-cilia defects","journal":"Veterinary pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined differential phenotype across multiple organ systems, single lab","pmids":["20080492"],"is_preprint":false},{"year":2002,"finding":"PKD1L1 encodes a 2849-amino-acid polycystin-1-like protein with two Ig-like PKD domains, a REJ domain, a GPS motif, a LH2/PLAT domain, a coiled-coil domain, and 11 putative transmembrane domains; it is expressed in human testis, fetal and adult heart, and in mouse Leydig cells of the testis.","method":"Full-length cDNA sequencing from human testis; dot-blot and RT-PCR expression analysis; in situ hybridization; FISH chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequence determination plus multiple expression methods, single lab; domain architecture inferred from sequence homology","pmids":["11863367"],"is_preprint":false},{"year":2016,"finding":"Bi-allelic loss-of-function mutations in human PKD1L1 cause laterality defects (situs inversus totalis and heterotaxy with complex congenital heart malformations); a missense mutation p.Cys1691Ser disrupts a conserved cysteine in the GPS motif predicted to be required for a disulfide bridge essential for proper GPS-motif folding, establishing the GPS motif as functionally critical.","method":"Whole-exome sequencing of two unrelated families; molecular modelling of GPS motif disulfide bridge; splice-site mutation prediction","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — human genetics with molecular modelling; no in vitro reconstitution of the GPS disruption, but supported by parallel evidence from related polycystin-family GPS mutations","pmids":["27616478"],"is_preprint":false},{"year":2024,"finding":"Pkd1l1 deficiency in biliary epithelial cells reduces primary cilia on cholangiocytes, decreases expression of ciliary Hedgehog-pathway signalling genes (Gli1, Gli2, Ptch1, Ptch2), and increases fibrosis/ECM-remodelling genes (Tgfα, Cdkn1a, Hb-egf, Fgfr3, Pdgfc, Mmp12, Mmp15), leading to bile duct hypertrophy, fibrosis, and delayed biliary drainage; pharmacological inhibition of GLI1 with Gant61 recapitulates the Pkd1l1-deficient biliary phenotype, placing Pkd1l1 upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis.","method":"Constitutive and conditional Pkd1l1 knockout mice; cholangiography; DDC dietary challenge; immunofluorescence for primary cilia; gene expression analysis; GLI1 inhibitor (Gant61) pharmacological epistasis","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO, pharmacological epistasis, gene expression, histology) in a single lab","pmids":["38460793"],"is_preprint":false},{"year":2023,"finding":"Liver-specific (hepatoblast) deletion of Pkd1l1 causes reduced primary cilia on cholangiocytes, delayed biliary maturation, progressive cholangiocyte proliferation, peribiliary fibroinflammation, and arterial hypertrophy, demonstrating a cell-autonomous role for Pkd1l1 in intrahepatic biliary ciliogenesis and duct morphogenesis.","method":"CRISPR-based conditional loxP Pkd1l1 allele crossed with AFP-Cre for liver-specific knockout; immunofluorescence; electron microscopy; RNA sequencing; bile duct ligation challenge","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal analyses (EM, RNA-seq, histology, functional ligation challenge), single lab","pmids":["36645229"],"is_preprint":false},{"year":2023,"finding":"Loss of pkd1l1 in zebrafish causes left-right patterning defects and reduces biliary epithelial cell number and intrahepatic biliary network density, demonstrating a conserved role for Pkd1l1 in biliary tree development beyond laterality.","method":"CRISPR/Cas9-generated pkd1l1hsc117 zebrafish allele; fluorescent biliary functional assay (PED6 accumulation); immunofluorescence quantification of biliary epithelial cells","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR null allele with functional biliary assay and cell quantification, single lab","pmids":["37675454"],"is_preprint":false},{"year":2024,"finding":"PKD1L1 missense variants implicated in congenital chylothorax cause protein dysfunction without mislocalization, whereas a loss-of-function frameshift variant causes protein mislocalization; Pkd1l1 mutant mouse embryos display pleural effusion and altered lymphatic vessel morphology at E14.5, identifying a role for PKD1L1 in lymphatic vessel development.","method":"Exome sequencing; immunofluorescence assessment of PKD1L1 protein localization for identified variants; immunofluorescence staining of lymphatic vessels in Pkd1l1 mutant mouse embryos at E14.5","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, localization assay and embryo phenotyping without functional reconstitution or pathway placement for lymphatic role","pmids":["38247840"],"is_preprint":false}],"current_model":"PKD1L1 encodes a polycystin-1-like transmembrane protein that localises to cilia, where it forms a complex with Pkd2 (polycystin-2) to sense nodal flow and establish vertebrate left-right asymmetry; its GPS motif is required for proper protein folding, its ciliary presence is required for Hedgehog/GLI signalling in cholangiocytes to maintain bile duct homeostasis, and it also plays a role in lymphatic vessel development, with bi-allelic loss-of-function mutations in humans causing heterotaxy, congenital heart disease, and biliary atresia splenic malformation syndrome."},"narrative":{"mechanistic_narrative":"PKD1L1 encodes a large polycystin-1-like transmembrane protein, with two Ig-like PKD domains, a REJ domain, a GPS motif, a LH2/PLAT domain, a coiled-coil domain, and multiple putative transmembrane segments, expressed in testis and heart [PMID:11863367]. Its central characterized function is in establishing vertebrate left-right asymmetry: PKD1L1 physically interacts with and co-localizes with PKD2 (polycystin-2) in node/Kupffer's vesicle cilia, where the PKD1L1-PKD2 complex acts downstream of nodal flow to trigger asymmetric gene expression, and loss of PKD1L1 phenocopies loss of PKD2 [PMID:21307093, PMID:21307098]. This sensory function operates within motile cilia that carry the complex, rather than a separate immotile population [PMID:21307098], with PKD1L1 loss producing laterality defects without the motile-cilia comorbidities seen in classic ciliopathies [PMID:20080492]. Beyond laterality, PKD1L1 supports primary ciliogenesis on cholangiocytes and acts upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis; its loss reduces cholangiocyte cilia and Hedgehog-pathway gene expression while driving fibrosis and abnormal duct morphogenesis, a phenotype recapitulated by GLI1 inhibition [PMID:38460793, PMID:36645229, PMID:37675454]. Bi-allelic loss-of-function PKD1L1 mutations in humans cause laterality defects with complex congenital heart malformation, and a missense substitution disrupting a conserved GPS-motif cysteine establishes the GPS motif as critical for protein function [PMID:27616478].","teleology":[{"year":2002,"claim":"Established the molecular identity of PKD1L1 as a polycystin-1-like multidomain transmembrane protein, defining the domain architecture that frames all later mechanistic work.","evidence":"Full-length cDNA sequencing from human testis with expression mapping and FISH chromosomal localization","pmids":["11863367"],"confidence":"Medium","gaps":["Domain architecture inferred from sequence homology, not structurally resolved","No functional assay for any domain","Cellular and ciliary localization not yet examined"]},{"year":2010,"claim":"Showed that PKD1L1 loss causes laterality defects via sensory (immotile) cilium dysfunction rather than motile-cilia failure, distinguishing it from classic motile ciliopathies.","evidence":"Constitutive Pkd1l1-knockout mouse with phenotype battery and comparative pathology against motile-cilia mutants","pmids":["20080492"],"confidence":"Medium","gaps":["Molecular partner mediating the sensory function not identified here","Single lab","Direct demonstration of ciliary localization not provided"]},{"year":2011,"claim":"Defined the core mechanism: PKD1L1 forms a ciliary complex with PKD2 that acts downstream of nodal flow as the left-right symmetry-breaking sensor, resolving how the protein transduces flow into asymmetric gene expression.","evidence":"Co-immunoprecipitation, ciliary co-localization, and genetic epistasis via matched Pkd1l1/Pkd2 mutant phenocopying in mouse, plus positional cloning of the medaka abc mutant with interaction and motility analysis","pmids":["21307093","21307098"],"confidence":"High","gaps":["Whether the complex senses mechanical flow versus a chemical signal not resolved","Channel activity / ion conductance of the complex not directly measured","Stoichiometry and structure of the PKD1L1-PKD2 complex unknown"]},{"year":2016,"claim":"Connected PKD1L1 to human disease and pinpointed the GPS motif as functionally essential, showing that bi-allelic loss of function causes heterotaxy and congenital heart disease.","evidence":"Whole-exome sequencing of two families with molecular modelling of a GPS-motif disulfide bridge","pmids":["27616478"],"confidence":"Medium","gaps":["GPS disruption not reconstituted in vitro","Effect of GPS mutation on PKD2 interaction not tested","Mechanism linking GPS folding to ciliary function inferred from modelling"]},{"year":2023,"claim":"Extended PKD1L1 function beyond laterality to biliary tree development, establishing a cell-autonomous role in cholangiocyte ciliogenesis and duct morphogenesis conserved across species.","evidence":"Liver-specific conditional Pkd1l1 knockout mice (EM, RNA-seq, ligation challenge) and CRISPR pkd1l1 null zebrafish with biliary functional assay","pmids":["36645229","37675454"],"confidence":"Medium","gaps":["Molecular signalling pathway downstream of biliary cilia not yet identified in these studies","Whether PKD2 partnership operates in cholangiocytes untested","Single lab per model"]},{"year":2024,"claim":"Placed PKD1L1 upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis, providing a pathway mechanism for the biliary phenotype.","evidence":"Constitutive and conditional Pkd1l1 knockout mice with cholangiography, gene expression profiling, and GLI1-inhibitor (Gant61) pharmacological epistasis","pmids":["38460793"],"confidence":"Medium","gaps":["Direct molecular link between PKD1L1 and Hedgehog component activation not defined","Whether the effect is solely via cilium loss or a direct signalling role unresolved","Single lab"]},{"year":2024,"claim":"Implicated PKD1L1 in lymphatic vessel development, broadening its physiological roles, with variant-specific effects on protein localization.","evidence":"Exome sequencing of congenital chylothorax cases with PKD1L1 localization assays and lymphatic-vessel immunofluorescence in mutant mouse embryos","pmids":["38247840"],"confidence":"Low","gaps":["No functional reconstitution or pathway placement for the lymphatic role","Mechanism connecting PKD1L1 to lymphatic morphogenesis unknown","Single lab, descriptive phenotyping"]},{"year":null,"claim":"How the PKD1L1-PKD2 complex physically transduces nodal flow into intracellular signalling, and whether its biliary and lymphatic roles depend on the same complex and channel mechanism, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of the PKD1L1-PKD2 complex","Ion-conductance / mechanosensory activity not directly measured","Tissue-specific partners for biliary and lymphatic functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,5,6]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,6,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]}],"complexes":["PKD1L1-PKD2 polycystin complex"],"partners":["PKD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TDX9","full_name":"Polycystin-1-like protein 1","aliases":["PC1-like 1 protein","Polycystic kidney disease protein 1-like 1"],"length_aa":2849,"mass_kda":315.4,"function":"Component of a calcium-permeant ion channel formed by PKD1L2 and PKD1L1 in primary cilia, where it controls cilium calcium concentration, without affecting cytoplasmic calcium concentration, and regulates sonic hedgehog/SHH signaling and GLI2 transcription (PubMed:24336289). The PKD1L1:PKD2L1 channel complex is mechanosensitive only at high pressures and is highly temperature sensitive (PubMed:24336289). Also involved in left/right axis specification downstream of nodal flow by forming a complex with PKD2 in cilia to facilitate flow detection in left/right patterning (By similarity). May function as a G-protein-coupled receptor (PubMed:15203210)","subcellular_location":"Cell projection, cilium membrane","url":"https://www.uniprot.org/uniprotkb/Q8TDX9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PKD1L1","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/PKD1L1","total_profiled":1310},"omim":[{"mim_id":"617205","title":"HETEROTAXY, VISCERAL, 8, AUTOSOMAL; HTX8","url":"https://www.omim.org/entry/617205"},{"mim_id":"609721","title":"POLYCYSTIN 1-LIKE 1; PKD1L1","url":"https://www.omim.org/entry/609721"},{"mim_id":"609068","title":"DAN DOMAIN FAMILY, MEMBER 5; DAND5","url":"https://www.omim.org/entry/609068"},{"mim_id":"607894","title":"POLYCYSTIN 1-LIKE 2; PKD1L2","url":"https://www.omim.org/entry/607894"},{"mim_id":"604532","title":"POLYCYSTIN 2-LIKE 1; PKD2L1","url":"https://www.omim.org/entry/604532"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"skeletal muscle","ntpm":2.6},{"tissue":"tongue","ntpm":2.4}],"url":"https://www.proteinatlas.org/search/PKD1L1"},"hgnc":{"alias_symbol":["PRO19563"],"prev_symbol":[]},"alphafold":{"accession":"Q8TDX9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDX9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDX9-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TDX9-2-F1-predicted_aligned_error_v6.png","plddt_mean":58.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PKD1L1","jax_strain_url":"https://www.jax.org/strain/search?query=PKD1L1"},"sequence":{"accession":"Q8TDX9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TDX9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TDX9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TDX9"}},"corpus_meta":[{"pmid":"21307093","id":"PMC_21307093","title":"Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2.","date":"2011","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21307093","citation_count":145,"is_preprint":false},{"pmid":"21307098","id":"PMC_21307098","title":"Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left-right axis.","date":"2011","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21307098","citation_count":105,"is_preprint":false},{"pmid":"20080492","id":"PMC_20080492","title":"Situs inversus in Dpcd/Poll-/-, Nme7-/- , and Pkd1l1-/- mice.","date":"2010","source":"Veterinary pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20080492","citation_count":73,"is_preprint":false},{"pmid":"27616478","id":"PMC_27616478","title":"Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27616478","citation_count":61,"is_preprint":false},{"pmid":"11863367","id":"PMC_11863367","title":"The sequence, expression, and chromosomal localization of a novel polycystic kidney disease 1-like gene, PKD1L1, in human.","date":"2002","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11863367","citation_count":40,"is_preprint":false},{"pmid":"38460793","id":"PMC_38460793","title":"Pkd1l1-deficiency drives biliary atresia through ciliary dysfunction in biliary epithelial cells.","date":"2024","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/38460793","citation_count":20,"is_preprint":false},{"pmid":"36645229","id":"PMC_36645229","title":"Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy.","date":"2023","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/36645229","citation_count":20,"is_preprint":false},{"pmid":"31026592","id":"PMC_31026592","title":"Compound heterozygous Pkd1l1 variants in a family with two fetuses affected by heterotaxy and complex Chd.","date":"2019","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31026592","citation_count":12,"is_preprint":false},{"pmid":"33655537","id":"PMC_33655537","title":"Hydrops fetalis in PKD1L1-related heterotaxy: Report of two foetuses and expanding the phenotypic and molecular spectrum.","date":"2021","source":"Annals of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33655537","citation_count":6,"is_preprint":false},{"pmid":"37675454","id":"PMC_37675454","title":"Loss of zebrafish pkd1l1 causes biliary defects that have implications for biliary atresia splenic malformation.","date":"2023","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/37675454","citation_count":5,"is_preprint":false},{"pmid":"37607472","id":"PMC_37607472","title":"Traveling to the left: A story of PKD1L1-containing vesicles.","date":"2023","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/37607472","citation_count":1,"is_preprint":false},{"pmid":"38247840","id":"PMC_38247840","title":"PKD1L1 Is Involved in Congenital Chylothorax.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/38247840","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8242,"output_tokens":2597,"usd":0.031841,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9786,"output_tokens":2831,"usd":0.059853,"stage2_stop_reason":"end_turn"},"total_usd":0.091694,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Pkd1l1 physically interacts with Pkd2 (co-immunoprecipitation), co-localises with Pkd2 in the cilium of mouse node cells, and both proteins act downstream of nodal flow to establish left-right asymmetry; loss of Pkd1l1 phenocopies loss of Pkd2, with failure to activate asymmetric gene expression at the node and in the lateral plate mesoderm, and right isomerism of the lungs, despite normal node/cilia morphology and motility.\",\n      \"method\": \"Biochemical co-immunoprecipitation, cell biological co-localisation in cilia, phenotypic comparison of Pkd1l1 and Pkd2 point mutants (mouse genetics)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical interaction plus ciliary co-localisation plus genetic epistasis via matched mutant phenocopying, replicated across two independent labs in the same issue\",\n      \"pmids\": [\"21307093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In medaka (zebrafish-related model), pkd1l1 is expressed exclusively in Kupffer's vesicle (KV); Pkd1l1 and Pkd2 interact and interdependently co-localise at motile KV cilia; all KV cilia contain Pkd1l1, Pkd2, and left-right dynein and are motile, indicating Pkd1l1-Pkd2 complexes function as the nodal flow sensor within motile cilia rather than in a separate immotile sensory population.\",\n      \"method\": \"Genetic mapping of medaka left-right mutant abecobe (abc) to pkd1l1; immunofluorescence co-localisation; interaction assay; ciliary motility analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning plus protein interaction plus co-localisation, independently replicating the mouse findings from the companion paper\",\n      \"pmids\": [\"21307098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pkd1l1-knockout mice develop situs inversus without hydrocephalus, sinusitis, or male infertility, indicating that Pkd1l1 loss causes laterality defects through dysfunction of mechanosensory (immotile) cilia rather than motile cilia, consistent with a sensory role analogous to Pkd1 in renal primary cilia.\",\n      \"method\": \"Constitutive Pkd1l1 knockout mouse; phenotype battery screening; comparative pathology with Dpcd/Poll and Nme7 knockouts that have motile-cilia defects\",\n      \"journal\": \"Veterinary pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined differential phenotype across multiple organ systems, single lab\",\n      \"pmids\": [\"20080492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PKD1L1 encodes a 2849-amino-acid polycystin-1-like protein with two Ig-like PKD domains, a REJ domain, a GPS motif, a LH2/PLAT domain, a coiled-coil domain, and 11 putative transmembrane domains; it is expressed in human testis, fetal and adult heart, and in mouse Leydig cells of the testis.\",\n      \"method\": \"Full-length cDNA sequencing from human testis; dot-blot and RT-PCR expression analysis; in situ hybridization; FISH chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequence determination plus multiple expression methods, single lab; domain architecture inferred from sequence homology\",\n      \"pmids\": [\"11863367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bi-allelic loss-of-function mutations in human PKD1L1 cause laterality defects (situs inversus totalis and heterotaxy with complex congenital heart malformations); a missense mutation p.Cys1691Ser disrupts a conserved cysteine in the GPS motif predicted to be required for a disulfide bridge essential for proper GPS-motif folding, establishing the GPS motif as functionally critical.\",\n      \"method\": \"Whole-exome sequencing of two unrelated families; molecular modelling of GPS motif disulfide bridge; splice-site mutation prediction\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — human genetics with molecular modelling; no in vitro reconstitution of the GPS disruption, but supported by parallel evidence from related polycystin-family GPS mutations\",\n      \"pmids\": [\"27616478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Pkd1l1 deficiency in biliary epithelial cells reduces primary cilia on cholangiocytes, decreases expression of ciliary Hedgehog-pathway signalling genes (Gli1, Gli2, Ptch1, Ptch2), and increases fibrosis/ECM-remodelling genes (Tgfα, Cdkn1a, Hb-egf, Fgfr3, Pdgfc, Mmp12, Mmp15), leading to bile duct hypertrophy, fibrosis, and delayed biliary drainage; pharmacological inhibition of GLI1 with Gant61 recapitulates the Pkd1l1-deficient biliary phenotype, placing Pkd1l1 upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis.\",\n      \"method\": \"Constitutive and conditional Pkd1l1 knockout mice; cholangiography; DDC dietary challenge; immunofluorescence for primary cilia; gene expression analysis; GLI1 inhibitor (Gant61) pharmacological epistasis\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO, pharmacological epistasis, gene expression, histology) in a single lab\",\n      \"pmids\": [\"38460793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Liver-specific (hepatoblast) deletion of Pkd1l1 causes reduced primary cilia on cholangiocytes, delayed biliary maturation, progressive cholangiocyte proliferation, peribiliary fibroinflammation, and arterial hypertrophy, demonstrating a cell-autonomous role for Pkd1l1 in intrahepatic biliary ciliogenesis and duct morphogenesis.\",\n      \"method\": \"CRISPR-based conditional loxP Pkd1l1 allele crossed with AFP-Cre for liver-specific knockout; immunofluorescence; electron microscopy; RNA sequencing; bile duct ligation challenge\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal analyses (EM, RNA-seq, histology, functional ligation challenge), single lab\",\n      \"pmids\": [\"36645229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of pkd1l1 in zebrafish causes left-right patterning defects and reduces biliary epithelial cell number and intrahepatic biliary network density, demonstrating a conserved role for Pkd1l1 in biliary tree development beyond laterality.\",\n      \"method\": \"CRISPR/Cas9-generated pkd1l1hsc117 zebrafish allele; fluorescent biliary functional assay (PED6 accumulation); immunofluorescence quantification of biliary epithelial cells\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR null allele with functional biliary assay and cell quantification, single lab\",\n      \"pmids\": [\"37675454\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PKD1L1 missense variants implicated in congenital chylothorax cause protein dysfunction without mislocalization, whereas a loss-of-function frameshift variant causes protein mislocalization; Pkd1l1 mutant mouse embryos display pleural effusion and altered lymphatic vessel morphology at E14.5, identifying a role for PKD1L1 in lymphatic vessel development.\",\n      \"method\": \"Exome sequencing; immunofluorescence assessment of PKD1L1 protein localization for identified variants; immunofluorescence staining of lymphatic vessels in Pkd1l1 mutant mouse embryos at E14.5\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization assay and embryo phenotyping without functional reconstitution or pathway placement for lymphatic role\",\n      \"pmids\": [\"38247840\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PKD1L1 encodes a polycystin-1-like transmembrane protein that localises to cilia, where it forms a complex with Pkd2 (polycystin-2) to sense nodal flow and establish vertebrate left-right asymmetry; its GPS motif is required for proper protein folding, its ciliary presence is required for Hedgehog/GLI signalling in cholangiocytes to maintain bile duct homeostasis, and it also plays a role in lymphatic vessel development, with bi-allelic loss-of-function mutations in humans causing heterotaxy, congenital heart disease, and biliary atresia splenic malformation syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKD1L1 encodes a large polycystin-1-like transmembrane protein, with two Ig-like PKD domains, a REJ domain, a GPS motif, a LH2/PLAT domain, a coiled-coil domain, and multiple putative transmembrane segments, expressed in testis and heart [#3]. Its central characterized function is in establishing vertebrate left-right asymmetry: PKD1L1 physically interacts with and co-localizes with PKD2 (polycystin-2) in node/Kupffer's vesicle cilia, where the PKD1L1-PKD2 complex acts downstream of nodal flow to trigger asymmetric gene expression, and loss of PKD1L1 phenocopies loss of PKD2 [#0, #1]. This sensory function operates within motile cilia that carry the complex, rather than a separate immotile population [#1], with PKD1L1 loss producing laterality defects without the motile-cilia comorbidities seen in classic ciliopathies [#2]. Beyond laterality, PKD1L1 supports primary ciliogenesis on cholangiocytes and acts upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis; its loss reduces cholangiocyte cilia and Hedgehog-pathway gene expression while driving fibrosis and abnormal duct morphogenesis, a phenotype recapitulated by GLI1 inhibition [#5, #6, #7]. Bi-allelic loss-of-function PKD1L1 mutations in humans cause laterality defects with complex congenital heart malformation, and a missense substitution disrupting a conserved GPS-motif cysteine establishes the GPS motif as critical for protein function [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the molecular identity of PKD1L1 as a polycystin-1-like multidomain transmembrane protein, defining the domain architecture that frames all later mechanistic work.\",\n      \"evidence\": \"Full-length cDNA sequencing from human testis with expression mapping and FISH chromosomal localization\",\n      \"pmids\": [\"11863367\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain architecture inferred from sequence homology, not structurally resolved\", \"No functional assay for any domain\", \"Cellular and ciliary localization not yet examined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed that PKD1L1 loss causes laterality defects via sensory (immotile) cilium dysfunction rather than motile-cilia failure, distinguishing it from classic motile ciliopathies.\",\n      \"evidence\": \"Constitutive Pkd1l1-knockout mouse with phenotype battery and comparative pathology against motile-cilia mutants\",\n      \"pmids\": [\"20080492\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partner mediating the sensory function not identified here\", \"Single lab\", \"Direct demonstration of ciliary localization not provided\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the core mechanism: PKD1L1 forms a ciliary complex with PKD2 that acts downstream of nodal flow as the left-right symmetry-breaking sensor, resolving how the protein transduces flow into asymmetric gene expression.\",\n      \"evidence\": \"Co-immunoprecipitation, ciliary co-localization, and genetic epistasis via matched Pkd1l1/Pkd2 mutant phenocopying in mouse, plus positional cloning of the medaka abc mutant with interaction and motility analysis\",\n      \"pmids\": [\"21307093\", \"21307098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the complex senses mechanical flow versus a chemical signal not resolved\", \"Channel activity / ion conductance of the complex not directly measured\", \"Stoichiometry and structure of the PKD1L1-PKD2 complex unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PKD1L1 to human disease and pinpointed the GPS motif as functionally essential, showing that bi-allelic loss of function causes heterotaxy and congenital heart disease.\",\n      \"evidence\": \"Whole-exome sequencing of two families with molecular modelling of a GPS-motif disulfide bridge\",\n      \"pmids\": [\"27616478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GPS disruption not reconstituted in vitro\", \"Effect of GPS mutation on PKD2 interaction not tested\", \"Mechanism linking GPS folding to ciliary function inferred from modelling\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended PKD1L1 function beyond laterality to biliary tree development, establishing a cell-autonomous role in cholangiocyte ciliogenesis and duct morphogenesis conserved across species.\",\n      \"evidence\": \"Liver-specific conditional Pkd1l1 knockout mice (EM, RNA-seq, ligation challenge) and CRISPR pkd1l1 null zebrafish with biliary functional assay\",\n      \"pmids\": [\"36645229\", \"37675454\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signalling pathway downstream of biliary cilia not yet identified in these studies\", \"Whether PKD2 partnership operates in cholangiocytes untested\", \"Single lab per model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PKD1L1 upstream of ciliary Hedgehog/GLI1 signalling in bile duct homeostasis, providing a pathway mechanism for the biliary phenotype.\",\n      \"evidence\": \"Constitutive and conditional Pkd1l1 knockout mice with cholangiography, gene expression profiling, and GLI1-inhibitor (Gant61) pharmacological epistasis\",\n      \"pmids\": [\"38460793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between PKD1L1 and Hedgehog component activation not defined\", \"Whether the effect is solely via cilium loss or a direct signalling role unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated PKD1L1 in lymphatic vessel development, broadening its physiological roles, with variant-specific effects on protein localization.\",\n      \"evidence\": \"Exome sequencing of congenital chylothorax cases with PKD1L1 localization assays and lymphatic-vessel immunofluorescence in mutant mouse embryos\",\n      \"pmids\": [\"38247840\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional reconstitution or pathway placement for the lymphatic role\", \"Mechanism connecting PKD1L1 to lymphatic morphogenesis unknown\", \"Single lab, descriptive phenotyping\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the PKD1L1-PKD2 complex physically transduces nodal flow into intracellular signalling, and whether its biliary and lymphatic roles depend on the same complex and channel mechanism, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure of the PKD1L1-PKD2 complex\", \"Ion-conductance / mechanosensory activity not directly measured\", \"Tissue-specific partners for biliary and lymphatic functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 6, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"PKD1L1-PKD2 polycystin complex\"],\n    \"partners\": [\"PKD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}