{"gene":"WDR19","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2006,"finding":"C. elegans DYF-2 (WDR19 ortholog) is a component of the IFT machinery in sensory cilia; loss of DYF-2 selectively affects assembly and motility of different IFT components and leads to cilia structural defects and chemosensation defects. DYF-2 associates with IFT complex B, and mutations in dyf-2 also interfere with complex A function, suggesting a role in IFT particle assembly as a whole. The mouse ortholog WDR19 localizes to cilia.","method":"Transgenic rescue of mutant phenotypes, sequencing of mutant alleles, fluorescence imaging of IFT component movement, Bardet-Biedl syndrome double-mutant analysis (genetic epistasis), localization of mouse WDR19 to cilia","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (rescue, epistasis, live imaging in model organism) with rigorous controls; replicated in mouse localization","pmids":["16957054"],"is_preprint":false},{"year":2011,"finding":"WDR19 encodes IFT144, a member of IFT complex A that drives retrograde ciliary transport. In fibroblasts from a Sensenbrenner syndrome patient with WDR19 mutations, IFT144 protein is absent from cilia and ciliary abundance and morphology are perturbed, demonstrating ciliary pathogenesis.","method":"Exome sequencing to identify mutations; immunofluorescence of patient-derived fibroblasts to assess ciliary localization and morphology","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in patient cells with functional consequence (absent protein, disrupted cilia), single lab","pmids":["22019273"],"is_preprint":false},{"year":2021,"finding":"Compound heterozygous IFT144/WDR19 mutations (missense L710S and nonsense R1103*) cause severe ciliary defects via a specific mechanism: L710S is hypomorphic (partially rescues ciliogenesis and ciliary protein localization in IFT144-KO cells), while R1103* exacerbates ciliogenesis defects on its own but rescues defects when co-expressed with WT. Co-expression of R1103* with the hypomorphic L710S mimics the CED patient genotype and results in severe ciliogenesis defects. The two variants differ in their interactions with other IFT-A subunits and with the IFT-B complex.","method":"IFT144-knockout (KO) cell lines, exogenous expression of WT and mutant IFT144 variants, ciliogenesis rescue assays, immunofluorescence for ciliary protein localization, co-immunoprecipitation to assess IFT-A and IFT-B interactions","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — KO cell reconstitution with multiple mutants, functional rescue assays, protein interaction studies; multiple orthogonal methods in a single rigorous study","pmids":["33517396"],"is_preprint":false},{"year":2020,"finding":"WDR19 localizes to the sperm neck and flagella; a homozygous missense mutation (p.K1271E) causes complete absence of WDR19 from sperm neck and flagella, leading to ultrastructural disorganization of sperm flagella microtubules and MMAF. IFT140 and IFT88 (predicted direct interactors of WDR19) are mis-allocated in WDR19-mutated sperm, indicating WDR19 is required for proper IFT complex assembly and localization in sperm flagella.","method":"Whole exome sequencing, immunofluorescence of patient sperm, scanning and transmission electron microscopy of sperm ultrastructure","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment in patient tissue with functional consequence and ultrastructural validation; single lab, two orthogonal methods (IF + EM)","pmids":["32323121"],"is_preprint":false},{"year":2015,"finding":"In control kidney tissue, WDR19 protein localizes along the luminal borders of renal tubular epithelium (consistent with ciliary localization). In kidneys of NPHP13 patients with WDR19 mutations, the protein shows diffuse cytoplasmic staining instead, indicating that pathogenic mutations alter the subcellular localization of WDR19 in kidney cells.","method":"Immunohistochemistry on patient kidney biopsy tissue and control kidney tissue","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization method (IHC) in patient tissue, single lab, no functional rescue","pmids":["25726036"],"is_preprint":false},{"year":2020,"finding":"A synonymous variant in bovine WDR19 (BTA6:58373887C>T) activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from the WDR19 protein and decreases protein expression, resulting in compromised semen quality and male fertility.","method":"Genome-wide association study, whole-genome sequencing, bioinformatic splice-site analysis, transcription analysis (mRNA), Western blot for protein expression","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (GWAS, transcriptomics, Western blot) in bovine model, single lab","pmids":["32407316"],"is_preprint":false},{"year":2025,"finding":"A hypomorphic WDR19 variant (p.Cys293Tyr) impairs nephron development in kidney organoids, causing delayed differentiation, cystogenesis, and structural abnormalities in tubular and glomerular structures. Mutant organoids show reduced ciliation and shortened cilia. Both hypomorphic and loss-of-function WDR19 variants dysregulate Sonic hedgehog (Shh) signaling; severe loss-of-function upregulates Shh and significantly reduces ciliation, which is associated with downregulation of FGF8 and alterations in associated transcriptomic pathways.","method":"CRISPR-Cas9 engineering of patient-specific variants in human embryonic stem cells (hESCs), patient-derived iPSC differentiation into kidney organoids, immunofluorescence, electron microscopy, RNA-sequencing and pathway analysis","journal":"Kidney international reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (CRISPR KO/hypomorph, organoids, IF, EM, RNAseq) in a single study; single lab","pmids":["41141533"],"is_preprint":false},{"year":2003,"finding":"WDR19 encodes a WD-repeat protein containing six WD repeats, a clathrin heavy-chain repeat, and three transmembrane domains. It is expressed in prostate epithelium, regulated by androgenic hormones, and exhibits alternative splicing producing two prostate-restricted isoforms.","method":"cDNA cloning, sequence analysis, RNA in situ hybridization, androgen regulation assay in prostate tissue","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct expression and domain characterization experiments; single lab, multiple methods","pmids":["12906858"],"is_preprint":false}],"current_model":"WDR19 (IFT144) is a WD-repeat protein and core subunit of the intraflagellar transport complex A (IFT-A) that mediates retrograde ciliary transport; it is required for the proper assembly and motility of the IFT machinery, ciliary biogenesis, and correct localization of other IFT subunits (IFT140, IFT88) in cilia and flagella, with loss-of-function causing absent or structurally abnormal cilia, dysregulation of Sonic hedgehog signaling during kidney development, and a broad spectrum of ciliopathies depending on allele severity."},"narrative":{"mechanistic_narrative":"WDR19 (IFT144) is a WD-repeat protein that functions as a core subunit of the intraflagellar transport complex A (IFT-A), the machinery that drives retrograde ciliary transport and is required for ciliary biogenesis and integrity [PMID:16957054, PMID:22019273]. First defined through its C. elegans ortholog DYF-2, the protein is a component of the IFT machinery whose loss disrupts assembly and motility of distinct IFT components and produces structural cilia and chemosensation defects, with genetic interactions implicating it in IFT particle assembly across both complex A and complex B [PMID:16957054]. WDR19 localizes to cilia and is required for proper allocation of other IFT subunits, including its predicted direct interactors IFT140 and IFT88, which become mislocalized when WDR19 is absent [PMID:32323121]. Pathogenic WDR19 mutations abolish or redistribute the protein from the ciliary compartment and perturb ciliary abundance and morphology in patient fibroblasts, sperm flagella, and kidney epithelium, establishing a ciliary basis for disease [PMID:22019273, PMID:32323121, PMID:25726036]. Reconstitution in IFT144-knockout cells distinguishes hypomorphic from loss-of-function alleles, which differ in their interactions with IFT-A and IFT-B subunits and combine to produce graded ciliogenesis defects matching patient genotypes [PMID:33517396]. In kidney organoid models, both hypomorphic and loss-of-function variants reduce ciliation and dysregulate Sonic hedgehog signaling, with severe loss-of-function upregulating Shh and downregulating FGF8, impairing nephron development and causing cystogenesis [PMID:41141533]. These molecular defects underlie a spectrum of ciliopathies including Sensenbrenner/cranioectodermal dysplasia and NPHP13 nephronophthisis, as well as MMAF-associated male infertility [PMID:22019273, PMID:33517396, PMID:32323121, PMID:25726036].","teleology":[{"year":2006,"claim":"Established WDR19 (via the C. elegans ortholog DYF-2) as a genuine component of the intraflagellar transport machinery, answering whether the protein acts within cilia and how it relates to IFT complexes A and B.","evidence":"Transgenic rescue, allele sequencing, live imaging of IFT component movement and BBS double-mutant epistasis in C. elegans, plus mouse WDR19 ciliary localization","pmids":["16957054"],"confidence":"High","gaps":["Direct biochemical demonstration of IFT-A subunit composition in mammals not shown","Distinct contributions to anterograde versus retrograde transport not resolved","Human protein function inferred from ortholog, not directly tested here"]},{"year":2003,"claim":"Provided the first molecular characterization of human WDR19, defining its WD-repeat and clathrin heavy-chain repeat domain architecture and androgen-regulated prostate expression before its ciliary role was known.","evidence":"cDNA cloning, sequence analysis, RNA in situ hybridization and androgen regulation assay in prostate tissue","pmids":["12906858"],"confidence":"Medium","gaps":["No functional link between prostate expression and ciliary biology established","Functional role of the reported transmembrane domains not characterized","Significance of the prostate-restricted splice isoforms unknown"]},{"year":2011,"claim":"Connected WDR19/IFT144 mutations to human ciliopathy by showing loss of the protein from cilia in patient cells, answering whether disease mutations act through a ciliary mechanism.","evidence":"Exome sequencing and immunofluorescence of Sensenbrenner syndrome patient-derived fibroblasts","pmids":["22019273"],"confidence":"Medium","gaps":["Single lab, descriptive localization without functional rescue","Mechanism linking absent protein to altered ciliary morphology not dissected"]},{"year":2015,"claim":"Showed that pathogenic WDR19 mutations redistribute the protein from the ciliary border to diffuse cytoplasm in kidney, linking mislocalization to nephronophthisis (NPHP13).","evidence":"Immunohistochemistry on NPHP13 patient and control kidney biopsy tissue","pmids":["25726036"],"confidence":"Low","gaps":["Single localization method (IHC) in patient tissue with no functional rescue","Causality between mislocalization and tubular pathology not established","No quantification of ciliary defect"]},{"year":2020,"claim":"Extended WDR19 function to sperm flagella, demonstrating it is required for proper IFT subunit allocation (IFT140, IFT88) and flagellar microtubule organization, explaining a male infertility (MMAF) phenotype.","evidence":"Whole exome sequencing, immunofluorescence and scanning/transmission electron microscopy of patient sperm","pmids":["32323121"],"confidence":"Medium","gaps":["Direct physical interaction with IFT140/IFT88 inferred, not biochemically demonstrated here","Single patient/single lab without rescue","Tissue-specific requirements versus shared ciliary mechanism not separated"]},{"year":2020,"claim":"Demonstrated in a bovine model that even a synonymous WDR19 variant compromising splicing and protein level reduces semen quality, reinforcing a dose-dependent requirement for WDR19 in male fertility.","evidence":"GWAS, whole-genome sequencing, splice-site analysis, mRNA transcription analysis and Western blot in cattle","pmids":["32407316"],"confidence":"Medium","gaps":["Ciliary/flagellar mechanism not directly imaged in this study","Relevance of bovine finding to human alleles not tested"]},{"year":2021,"claim":"Resolved how compound heterozygous alleles combine to cause disease, distinguishing hypomorphic from loss-of-function variants by their differential ciliogenesis rescue and altered IFT-A/IFT-B interactions.","evidence":"IFT144-knockout cell reconstitution with WT and mutant variants, ciliogenesis rescue assays, immunofluorescence and co-immunoprecipitation for IFT-A and IFT-B interactions","pmids":["33517396"],"confidence":"High","gaps":["Which specific IFT-A/IFT-B contacts are lost for each variant not mapped at residue level","Structural basis of variant-specific interaction changes not determined"]},{"year":2025,"claim":"Linked WDR19 dysfunction to a downstream signaling defect, showing both hypomorphic and loss-of-function variants reduce ciliation and dysregulate Sonic hedgehog signaling to impair nephron development.","evidence":"CRISPR-Cas9 engineering of patient variants in hESCs, patient iPSC-derived kidney organoids, immunofluorescence, electron microscopy and RNA-sequencing pathway analysis","pmids":["41141533"],"confidence":"Medium","gaps":["Mechanistic link between IFT-A retrograde transport and Shh/FGF8 dysregulation not directly traced","Single lab organoid model; in vivo kidney correlation not established","Allele-specific severity gradient not fully mapped to transport defects"]},{"year":null,"claim":"How WDR19 physically organizes IFT-A architecture at the structural level and how disrupted retrograde transport mechanistically translates into Shh signaling dysregulation across tissues remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of WDR19 within the IFT-A complex in the corpus","Direct biochemical mapping of WDR19-IFT140/IFT88 contacts not established","Causal chain from IFT-A defect to Shh/FGF8 transcriptional changes not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]}],"complexes":["IFT-A complex","intraflagellar transport (IFT) machinery"],"partners":["IFT140","IFT88"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NEZ3","full_name":"WD repeat-containing protein 19","aliases":["Intraflagellar transport 144 homolog"],"length_aa":1342,"mass_kda":151.6,"function":"As component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in cilia function and/or assembly (PubMed:20889716). Essential for functional IFT-A assembly and ciliary entry of GPCRs (PubMed:20889716). Associates with the BBSome complex to mediate ciliary transport (By similarity)","subcellular_location":"Cell projection, cilium; Cytoplasm, cytoskeleton, cilium basal body; Cell projection, cilium, photoreceptor outer segment; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q8NEZ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR19","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDR19","total_profiled":1310},"omim":[{"mim_id":"619867","title":"SPERMATOGENIC FAILURE 72; SPGF72","url":"https://www.omim.org/entry/619867"},{"mim_id":"616307","title":"SENIOR-LOKEN SYNDROME 8; SLSN8","url":"https://www.omim.org/entry/616307"},{"mim_id":"615462","title":"DYNEIN, CYTOPLASMIC 2, INTERMEDIATE CHAIN 1; DYNC2I1","url":"https://www.omim.org/entry/615462"},{"mim_id":"614378","title":"CRANIOECTODERMAL DYSPLASIA 4; CED4","url":"https://www.omim.org/entry/614378"},{"mim_id":"614377","title":"NEPHRONOPHTHISIS 13; NPHP13","url":"https://www.omim.org/entry/614377"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Mid piece","reliability":"Uncertain"},{"location":"Centrosome","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR19"},"hgnc":{"alias_symbol":["Pwdmp","KIAA1638","FLJ23127","ORF26","DYF-2","Oseg6","IFT144","NPHP13","FAP66","CFAP66"],"prev_symbol":[]},"alphafold":{"accession":"Q8NEZ3","domains":[{"cath_id":"2.130.10.10","chopping":"231-350","consensus_level":"medium","plddt":86.079,"start":231,"end":350},{"cath_id":"-","chopping":"1168-1241","consensus_level":"medium","plddt":86.5392,"start":1168,"end":1241},{"cath_id":"3.30.40","chopping":"1248-1309_1321-1342","consensus_level":"medium","plddt":83.4231,"start":1248,"end":1342},{"cath_id":"1.25.40","chopping":"1007-1101","consensus_level":"medium","plddt":76.1593,"start":1007,"end":1101}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NEZ3-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR19","jax_strain_url":"https://www.jax.org/strain/search?query=WDR19"},"sequence":{"accession":"Q8NEZ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NEZ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NEZ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NEZ3"}},"corpus_meta":[{"pmid":"22019273","id":"PMC_22019273","title":"Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22019273","citation_count":190,"is_preprint":false},{"pmid":"16957054","id":"PMC_16957054","title":"Caenorhabditis elegans DYF-2, an orthologue of human WDR19, is a component of the intraflagellar transport machinery in sensory cilia.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16957054","citation_count":60,"is_preprint":false},{"pmid":"23683095","id":"PMC_23683095","title":"WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome.","date":"2013","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23683095","citation_count":59,"is_preprint":false},{"pmid":"32323121","id":"PMC_32323121","title":"A novel homozygous mutation in WDR19 induces disorganization of microtubules in sperm flagella and nonsyndromic asthenoteratospermia.","date":"2020","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32323121","citation_count":43,"is_preprint":false},{"pmid":"24504730","id":"PMC_24504730","title":"Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies.","date":"2014","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/24504730","citation_count":37,"is_preprint":false},{"pmid":"32407316","id":"PMC_32407316","title":"Activation of cryptic splicing in bovine WDR19 is associated with reduced semen quality and male fertility.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32407316","citation_count":36,"is_preprint":false},{"pmid":"33517396","id":"PMC_33517396","title":"Molecular basis of ciliary defects caused by compound heterozygous IFT144/WDR19 mutations found in cranioectodermal dysplasia.","date":"2021","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33517396","citation_count":24,"is_preprint":false},{"pmid":"25726036","id":"PMC_25726036","title":"Nephronophthisis 13: implications of its association with Caroli disease and altered intracellular localization of WDR19 in the kidney.","date":"2015","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/25726036","citation_count":21,"is_preprint":false},{"pmid":"18316561","id":"PMC_18316561","title":"WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence.","date":"2008","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/18316561","citation_count":17,"is_preprint":false},{"pmid":"28621010","id":"PMC_28621010","title":"Diversity of renal phenotypes in patients with WDR19 mutations: Two case reports.","date":"2017","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/28621010","citation_count":16,"is_preprint":false},{"pmid":"12906858","id":"PMC_12906858","title":"Isolation and characterization of human and mouse WDR19,a novel WD-repeat protein exhibiting androgen-regulated expression in prostate epithelium.","date":"2003","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/12906858","citation_count":14,"is_preprint":false},{"pmid":"36833218","id":"PMC_36833218","title":"Stargardt-like Clinical Characteristics and Disease Course Associated with Variants in the WDR19 Gene.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/36833218","citation_count":6,"is_preprint":false},{"pmid":"38715676","id":"PMC_38715676","title":"A case report of intrahepatic bile duct dilatation caused by WDR19 gene mutation and presented as Caroli syndrome.","date":"2024","source":"Translational pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/38715676","citation_count":4,"is_preprint":false},{"pmid":"38163131","id":"PMC_38163131","title":"Compound heterozygous WDR19 variants associated with nephronophthisis, Caroli disease, refractory epilepsy and congenital bilateral central blindness: Case report.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38163131","citation_count":4,"is_preprint":false},{"pmid":"35937515","id":"PMC_35937515","title":"Is C1q nephropathy associated with a WDR19 gene mutation? A case report.","date":"2021","source":"Hippokratia","url":"https://pubmed.ncbi.nlm.nih.gov/35937515","citation_count":1,"is_preprint":false},{"pmid":"35362211","id":"PMC_35362211","title":"A unique pancreatic phenotype in a child with a WDR19-related ciliopathy: A case report and literature review of pancreatic involvement in ciliopathies.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35362211","citation_count":1,"is_preprint":false},{"pmid":"39967245","id":"PMC_39967245","title":"WDR19-associated retinopathy presenting with adult-onset Stargardt-like phenotype.","date":"2025","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39967245","citation_count":1,"is_preprint":false},{"pmid":"41141533","id":"PMC_41141533","title":"Elucidating Mechanisms of Hypomorphic WDR19-Related Kidney Failure.","date":"2025","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/41141533","citation_count":0,"is_preprint":false},{"pmid":"40183892","id":"PMC_40183892","title":"Phenotypic spectrum and theoretical prime editing analysis of WDR19-mediated retinal degeneration.","date":"2025","source":"Documenta ophthalmologica. Advances in ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/40183892","citation_count":0,"is_preprint":false},{"pmid":"40647705","id":"PMC_40647705","title":"Early-Onset Retinal Dysfunction Associated with Novel WDR19 Variants in Sensenbrenner Syndrome.","date":"2025","source":"Diagnostics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40647705","citation_count":0,"is_preprint":false},{"pmid":"41942325","id":"PMC_41942325","title":"[Clinical characteristics and genetic analysis of a case of ciliopathy caused by novel WDR19 gene variants].","date":"2026","source":"Zhonghua nei ke za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41942325","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13275,"output_tokens":2279,"usd":0.037005,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9329,"output_tokens":3336,"usd":0.065022,"stage2_stop_reason":"end_turn"},"total_usd":0.102027,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans DYF-2 (WDR19 ortholog) is a component of the IFT machinery in sensory cilia; loss of DYF-2 selectively affects assembly and motility of different IFT components and leads to cilia structural defects and chemosensation defects. DYF-2 associates with IFT complex B, and mutations in dyf-2 also interfere with complex A function, suggesting a role in IFT particle assembly as a whole. The mouse ortholog WDR19 localizes to cilia.\",\n      \"method\": \"Transgenic rescue of mutant phenotypes, sequencing of mutant alleles, fluorescence imaging of IFT component movement, Bardet-Biedl syndrome double-mutant analysis (genetic epistasis), localization of mouse WDR19 to cilia\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (rescue, epistasis, live imaging in model organism) with rigorous controls; replicated in mouse localization\",\n      \"pmids\": [\"16957054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR19 encodes IFT144, a member of IFT complex A that drives retrograde ciliary transport. In fibroblasts from a Sensenbrenner syndrome patient with WDR19 mutations, IFT144 protein is absent from cilia and ciliary abundance and morphology are perturbed, demonstrating ciliary pathogenesis.\",\n      \"method\": \"Exome sequencing to identify mutations; immunofluorescence of patient-derived fibroblasts to assess ciliary localization and morphology\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in patient cells with functional consequence (absent protein, disrupted cilia), single lab\",\n      \"pmids\": [\"22019273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound heterozygous IFT144/WDR19 mutations (missense L710S and nonsense R1103*) cause severe ciliary defects via a specific mechanism: L710S is hypomorphic (partially rescues ciliogenesis and ciliary protein localization in IFT144-KO cells), while R1103* exacerbates ciliogenesis defects on its own but rescues defects when co-expressed with WT. Co-expression of R1103* with the hypomorphic L710S mimics the CED patient genotype and results in severe ciliogenesis defects. The two variants differ in their interactions with other IFT-A subunits and with the IFT-B complex.\",\n      \"method\": \"IFT144-knockout (KO) cell lines, exogenous expression of WT and mutant IFT144 variants, ciliogenesis rescue assays, immunofluorescence for ciliary protein localization, co-immunoprecipitation to assess IFT-A and IFT-B interactions\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — KO cell reconstitution with multiple mutants, functional rescue assays, protein interaction studies; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"33517396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR19 localizes to the sperm neck and flagella; a homozygous missense mutation (p.K1271E) causes complete absence of WDR19 from sperm neck and flagella, leading to ultrastructural disorganization of sperm flagella microtubules and MMAF. IFT140 and IFT88 (predicted direct interactors of WDR19) are mis-allocated in WDR19-mutated sperm, indicating WDR19 is required for proper IFT complex assembly and localization in sperm flagella.\",\n      \"method\": \"Whole exome sequencing, immunofluorescence of patient sperm, scanning and transmission electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment in patient tissue with functional consequence and ultrastructural validation; single lab, two orthogonal methods (IF + EM)\",\n      \"pmids\": [\"32323121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In control kidney tissue, WDR19 protein localizes along the luminal borders of renal tubular epithelium (consistent with ciliary localization). In kidneys of NPHP13 patients with WDR19 mutations, the protein shows diffuse cytoplasmic staining instead, indicating that pathogenic mutations alter the subcellular localization of WDR19 in kidney cells.\",\n      \"method\": \"Immunohistochemistry on patient kidney biopsy tissue and control kidney tissue\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization method (IHC) in patient tissue, single lab, no functional rescue\",\n      \"pmids\": [\"25726036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A synonymous variant in bovine WDR19 (BTA6:58373887C>T) activates a cryptic exonic splice site that eliminates three evolutionarily conserved amino acids from the WDR19 protein and decreases protein expression, resulting in compromised semen quality and male fertility.\",\n      \"method\": \"Genome-wide association study, whole-genome sequencing, bioinformatic splice-site analysis, transcription analysis (mRNA), Western blot for protein expression\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (GWAS, transcriptomics, Western blot) in bovine model, single lab\",\n      \"pmids\": [\"32407316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A hypomorphic WDR19 variant (p.Cys293Tyr) impairs nephron development in kidney organoids, causing delayed differentiation, cystogenesis, and structural abnormalities in tubular and glomerular structures. Mutant organoids show reduced ciliation and shortened cilia. Both hypomorphic and loss-of-function WDR19 variants dysregulate Sonic hedgehog (Shh) signaling; severe loss-of-function upregulates Shh and significantly reduces ciliation, which is associated with downregulation of FGF8 and alterations in associated transcriptomic pathways.\",\n      \"method\": \"CRISPR-Cas9 engineering of patient-specific variants in human embryonic stem cells (hESCs), patient-derived iPSC differentiation into kidney organoids, immunofluorescence, electron microscopy, RNA-sequencing and pathway analysis\",\n      \"journal\": \"Kidney international reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (CRISPR KO/hypomorph, organoids, IF, EM, RNAseq) in a single study; single lab\",\n      \"pmids\": [\"41141533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"WDR19 encodes a WD-repeat protein containing six WD repeats, a clathrin heavy-chain repeat, and three transmembrane domains. It is expressed in prostate epithelium, regulated by androgenic hormones, and exhibits alternative splicing producing two prostate-restricted isoforms.\",\n      \"method\": \"cDNA cloning, sequence analysis, RNA in situ hybridization, androgen regulation assay in prostate tissue\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct expression and domain characterization experiments; single lab, multiple methods\",\n      \"pmids\": [\"12906858\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR19 (IFT144) is a WD-repeat protein and core subunit of the intraflagellar transport complex A (IFT-A) that mediates retrograde ciliary transport; it is required for the proper assembly and motility of the IFT machinery, ciliary biogenesis, and correct localization of other IFT subunits (IFT140, IFT88) in cilia and flagella, with loss-of-function causing absent or structurally abnormal cilia, dysregulation of Sonic hedgehog signaling during kidney development, and a broad spectrum of ciliopathies depending on allele severity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR19 (IFT144) is a WD-repeat protein that functions as a core subunit of the intraflagellar transport complex A (IFT-A), the machinery that drives retrograde ciliary transport and is required for ciliary biogenesis and integrity [#0, #1]. First defined through its C. elegans ortholog DYF-2, the protein is a component of the IFT machinery whose loss disrupts assembly and motility of distinct IFT components and produces structural cilia and chemosensation defects, with genetic interactions implicating it in IFT particle assembly across both complex A and complex B [#0]. WDR19 localizes to cilia and is required for proper allocation of other IFT subunits, including its predicted direct interactors IFT140 and IFT88, which become mislocalized when WDR19 is absent [#3]. Pathogenic WDR19 mutations abolish or redistribute the protein from the ciliary compartment and perturb ciliary abundance and morphology in patient fibroblasts, sperm flagella, and kidney epithelium, establishing a ciliary basis for disease [#1, #3, #4]. Reconstitution in IFT144-knockout cells distinguishes hypomorphic from loss-of-function alleles, which differ in their interactions with IFT-A and IFT-B subunits and combine to produce graded ciliogenesis defects matching patient genotypes [#2]. In kidney organoid models, both hypomorphic and loss-of-function variants reduce ciliation and dysregulate Sonic hedgehog signaling, with severe loss-of-function upregulating Shh and downregulating FGF8, impairing nephron development and causing cystogenesis [#6]. These molecular defects underlie a spectrum of ciliopathies including Sensenbrenner/cranioectodermal dysplasia and NPHP13 nephronophthisis, as well as MMAF-associated male infertility [#1, #2, #3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established WDR19 (via the C. elegans ortholog DYF-2) as a genuine component of the intraflagellar transport machinery, answering whether the protein acts within cilia and how it relates to IFT complexes A and B.\",\n      \"evidence\": \"Transgenic rescue, allele sequencing, live imaging of IFT component movement and BBS double-mutant epistasis in C. elegans, plus mouse WDR19 ciliary localization\",\n      \"pmids\": [\"16957054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical demonstration of IFT-A subunit composition in mammals not shown\",\n        \"Distinct contributions to anterograde versus retrograde transport not resolved\",\n        \"Human protein function inferred from ortholog, not directly tested here\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the first molecular characterization of human WDR19, defining its WD-repeat and clathrin heavy-chain repeat domain architecture and androgen-regulated prostate expression before its ciliary role was known.\",\n      \"evidence\": \"cDNA cloning, sequence analysis, RNA in situ hybridization and androgen regulation assay in prostate tissue\",\n      \"pmids\": [\"12906858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional link between prostate expression and ciliary biology established\",\n        \"Functional role of the reported transmembrane domains not characterized\",\n        \"Significance of the prostate-restricted splice isoforms unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected WDR19/IFT144 mutations to human ciliopathy by showing loss of the protein from cilia in patient cells, answering whether disease mutations act through a ciliary mechanism.\",\n      \"evidence\": \"Exome sequencing and immunofluorescence of Sensenbrenner syndrome patient-derived fibroblasts\",\n      \"pmids\": [\"22019273\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, descriptive localization without functional rescue\",\n        \"Mechanism linking absent protein to altered ciliary morphology not dissected\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that pathogenic WDR19 mutations redistribute the protein from the ciliary border to diffuse cytoplasm in kidney, linking mislocalization to nephronophthisis (NPHP13).\",\n      \"evidence\": \"Immunohistochemistry on NPHP13 patient and control kidney biopsy tissue\",\n      \"pmids\": [\"25726036\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single localization method (IHC) in patient tissue with no functional rescue\",\n        \"Causality between mislocalization and tubular pathology not established\",\n        \"No quantification of ciliary defect\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended WDR19 function to sperm flagella, demonstrating it is required for proper IFT subunit allocation (IFT140, IFT88) and flagellar microtubule organization, explaining a male infertility (MMAF) phenotype.\",\n      \"evidence\": \"Whole exome sequencing, immunofluorescence and scanning/transmission electron microscopy of patient sperm\",\n      \"pmids\": [\"32323121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction with IFT140/IFT88 inferred, not biochemically demonstrated here\",\n        \"Single patient/single lab without rescue\",\n        \"Tissue-specific requirements versus shared ciliary mechanism not separated\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated in a bovine model that even a synonymous WDR19 variant compromising splicing and protein level reduces semen quality, reinforcing a dose-dependent requirement for WDR19 in male fertility.\",\n      \"evidence\": \"GWAS, whole-genome sequencing, splice-site analysis, mRNA transcription analysis and Western blot in cattle\",\n      \"pmids\": [\"32407316\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ciliary/flagellar mechanism not directly imaged in this study\",\n        \"Relevance of bovine finding to human alleles not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved how compound heterozygous alleles combine to cause disease, distinguishing hypomorphic from loss-of-function variants by their differential ciliogenesis rescue and altered IFT-A/IFT-B interactions.\",\n      \"evidence\": \"IFT144-knockout cell reconstitution with WT and mutant variants, ciliogenesis rescue assays, immunofluorescence and co-immunoprecipitation for IFT-A and IFT-B interactions\",\n      \"pmids\": [\"33517396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific IFT-A/IFT-B contacts are lost for each variant not mapped at residue level\",\n        \"Structural basis of variant-specific interaction changes not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked WDR19 dysfunction to a downstream signaling defect, showing both hypomorphic and loss-of-function variants reduce ciliation and dysregulate Sonic hedgehog signaling to impair nephron development.\",\n      \"evidence\": \"CRISPR-Cas9 engineering of patient variants in hESCs, patient iPSC-derived kidney organoids, immunofluorescence, electron microscopy and RNA-sequencing pathway analysis\",\n      \"pmids\": [\"41141533\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between IFT-A retrograde transport and Shh/FGF8 dysregulation not directly traced\",\n        \"Single lab organoid model; in vivo kidney correlation not established\",\n        \"Allele-specific severity gradient not fully mapped to transport defects\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR19 physically organizes IFT-A architecture at the structural level and how disrupted retrograde transport mechanistically translates into Shh signaling dysregulation across tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of WDR19 within the IFT-A complex in the corpus\",\n        \"Direct biochemical mapping of WDR19-IFT140/IFT88 contacts not established\",\n        \"Causal chain from IFT-A defect to Shh/FGF8 transcriptional changes not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"IFT-A complex\",\n      \"intraflagellar transport (IFT) machinery\"\n    ],\n    \"partners\": [\n      \"IFT140\",\n      \"IFT88\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}