{"gene":"NPHS2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"NPHS2 encodes podocin, a novel integral membrane protein belonging to the stomatin protein family, almost exclusively expressed in podocytes of fetal and mature kidney glomeruli, identified by positional cloning as the causative gene for autosomal recessive steroid-resistant nephrotic syndrome.","method":"Positional cloning, sequence analysis, expression analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — positional cloning with multiple independent mutations (nonsense, frameshift, missense) segregating with disease; foundational discovery replicated across many subsequent studies","pmids":["10742096"],"is_preprint":false},{"year":2003,"finding":"Wild-type podocin forms homo-oligomers involving both carboxy and amino terminal cytoplasmic domains, and is targeted to plasma membrane lipid raft microdomains where it recruits nephrin into rafts. Disease-causing mutations R138Q and R138X fail to recruit nephrin into rafts: R138Q is retained in the endoplasmic reticulum, while R138X reaches the plasma membrane but fails to associate with rafts. Neither mutant augments nephrin signaling.","method":"Confocal microscopy, lipid raft fractionation, co-immunoprecipitation, site-directed mutagenesis, transfection in cell lines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, co-IP, confocal imaging, mutagenesis) in single rigorous study; findings on ER retention replicated by multiple subsequent labs","pmids":["14570703"],"is_preprint":false},{"year":2004,"finding":"Podocin biosynthesis follows the classical secretory (exocytic) pathway through the endoplasmic reticulum (demonstrated by brefeldin A treatment causing ER accumulation). Of 12 disease-causing NPHS2 mutations tested, 9 mutants failed to reach the plasma membrane: 8 were retained in the ER and 1 localized to late endosomes. Mutants retained in the ER are associated with earlier disease onset than those correctly targeted to the membrane.","method":"Brefeldin A treatment, confocal microscopy, subcellular fractionation, transfection in cell lines, genotype-phenotype correlation","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mutations tested with orthogonal methods (brefeldin A, confocal, fractionation); ER retention finding replicated independently","pmids":["14675423"],"is_preprint":false},{"year":2002,"finding":"The R229Q variant of podocin shows decreased binding to nephrin in vitro, providing a molecular mechanism by which this common polymorphism contributes to FSGS susceptibility.","method":"In vitro translation of podocin, pulldown assay with purified nephrin","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct binding assay with in vitro-translated proteins, single lab, single method","pmids":["12464671"],"is_preprint":false},{"year":2004,"finding":"Missense mutations in the proximal C-terminus of podocin (R138Q, V180M, R291W) cause aberrant subcellular localization: R138Q is retained in the ER, V180M forms cytoplasmic inclusion bodies, and R291W is trapped in the ER and small intracellular vesicles. This abnormal podocin localization also alters nephrin trafficking to the plasma membrane in cotransfected cells, due to direct protein-protein binding between podocin and nephrin.","method":"Site-directed mutagenesis, confocal microscopy, immunoprecipitation, pulldown assay, transfection in HEK293 cells","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (confocal, co-IP, pulldown, mutagenesis); findings on podocin-nephrin interaction and ER retention independently replicated","pmids":["15496146"],"is_preprint":false},{"year":2004,"finding":"In vivo, NPHS2 mutations cause profound alteration of podocin expression and/or subcellular distribution in patient kidney biopsies. Secondary changes in distribution of nephrin, CD2AP, and alpha-actinin occur in association with podocin defects, with these proteins redistributed from the glomerular basement membrane to the podocyte body, supporting a scaffolding role for podocin in organization of the slit diaphragm.","method":"Immunohistochemistry, in situ hybridization, renal biopsy analysis of patients with defined NPHS2 mutations","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct patient biopsy analysis with multiple slit diaphragm markers, multiple mutation types, single lab","pmids":["15327385"],"is_preprint":false},{"year":2014,"finding":"The pathogenicity of NPHS2 p.R229Q is mutation-dependent: it causes disease only when trans-associated with specific 3' NPHS2 mutations (affecting residues 270–351). These 3' mutations exert a dominant-negative effect on p.R229Q podocin through altered heterodimerization and mislocalization of the p.R229Q podocin, but behave as recessive alleles when associated with wild-type podocin.","method":"Clinical genetic analysis, protein heterodimerization assays, subcellular localization studies, structural modeling","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (heterodimerization assay, localization, genotype-phenotype in large cohort, structural analysis); published in Nature Genetics with rigorous evidence","pmids":["24509478"],"is_preprint":false},{"year":2015,"finding":"Nphs2 (podocin) is a direct transcriptional target of the Wilms' tumor suppressor WT1 in podocytes, identified by integration of chromatin immunoprecipitation sequencing (ChIP-seq) with transcriptomic analysis in WT1 knockout models, and functionally validated in zebrafish.","method":"ChIP-seq, cDNA microarray, Nphs2-Cre conditional WT1 knockout mice, zebrafish functional assays","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-seq plus transcriptomics plus in vivo KO model plus zebrafish validation; multiple orthogonal methods across species","pmids":["25556170"],"is_preprint":false},{"year":2006,"finding":"Three functional promoter polymorphisms of NPHS2 (-51T, -116T, and -535 insCTTTTTT3) cause strong downregulation of reporter gene expression in podocytes. Electrophoretic mobility shift assays showed that wild-type variants form specific DNA-protein complexes with podocyte nuclear extracts abolished by the rare forms. USF1 was identified as the specific trans-acting factor binding the -51G site, confirmed by binding inhibition and USF1 RNAi silencing.","method":"Reporter gene transfection in podocytes, EMSA, RNAi silencing of USF1, haplotype analysis","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus EMSA plus RNAi in single lab with multiple orthogonal methods","pmids":["16900088"],"is_preprint":false},{"year":2009,"finding":"The transcription factor Lmx1b regulates podocin (NPHS2) transcription by binding to a FLAT-F element in the promoter, demonstrating enhancer function. The SNP variant -116T in the promoter causes significant reduction in luciferase activity with altered nuclear protein binding.","method":"Reporter gene constructs, gel shift (EMSA) analysis, transfection in podocytes","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus EMSA in podocytes, single lab, two orthogonal methods","pmids":["19562271"],"is_preprint":false},{"year":2022,"finding":"In kidney organoids derived from iPSCs bearing endogenous NPHS2 pathogenic missense variants, distinct variants cause unique patterns of PODOCIN subcellular mistrafficking: P118L and R138Q are preferentially retained in the ER; R168H and R291W accumulate in the Golgi. All variants result in reduced PODOCIN protein levels without reduced transcription, variant-specific effects on NEPHRIN-PODOCIN colocalization and NEPHRIN trafficking, and podocyte-specific apoptosis not linked to ER stress.","method":"iPSC-derived kidney organoids, immunofluorescence, transcriptional profiling, PODOCIN-NEPHRIN colocalization assays, patient-derived iPSC lines","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous variants in physiologically relevant human podocyte organoid system, multiple variants with orthogonal methods (IF, transcriptomics, colocalization), patient-derived validation","pmids":["36167728"],"is_preprint":false},{"year":2016,"finding":"A heterozygous truncating mutation in NPHS2 (c.988_989delCT) causing dominant-pattern familial SRNS produces a truncated podocin that retains the ability to bind nephrin (by co-immunoprecipitation), but is associated with fragmented nephrin expression and reduced podocin expression in vivo.","method":"Co-immunoprecipitation, immunohistochemistry, whole genome sequencing, direct sequencing","journal":"Clinical and experimental nephrology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single co-IP experiment in single lab, limited mechanistic follow-up, single family","pmids":["27573339"],"is_preprint":false},{"year":2002,"finding":"Genetic epistasis between NPHS1 and NPHS2 was demonstrated: a 'tri-allelic' combination of NPHS1 and NPHS2 mutations modifies the phenotype from congenital nephrotic syndrome to congenital FSGS, providing functional evidence for a direct interaction between nephrin and podocin in the glomerular filtration barrier.","method":"Mutational analysis, genotype-phenotype epistasis in human patients","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic epistasis analysis across multiple families, replicated in subsequent studies; mechanism inferred from genotype-phenotype rather than biochemical reconstitution","pmids":["11854170"],"is_preprint":false}],"current_model":"NPHS2 encodes podocin, a stomatin-family integral membrane protein exclusively expressed in kidney podocytes, where it localizes to plasma membrane lipid raft microdomains at the slit diaphragm via the classical secretory pathway; podocin forms homo-oligomers and recruits nephrin into lipid rafts to facilitate nephrin signaling, while also scaffolding CD2AP and alpha-actinin at the slit diaphragm; most disease-causing mutations cause ER retention or mistargeting of podocin which secondarily mislocalizes nephrin and disrupts the slit diaphragm complex; podocin expression is transcriptionally regulated by WT1 and Lmx1b; and the pathogenicity of the common R229Q variant is mutation-dependent, causing disease only when trans-associated with specific C-terminal mutations through altered heterodimerization and mislocalization."},"narrative":{"mechanistic_narrative":"NPHS2 encodes podocin, a stomatin-family integral membrane protein almost exclusively expressed in kidney glomerular podocytes, where it was identified by positional cloning as the causative gene for autosomal recessive steroid-resistant nephrotic syndrome [PMID:10742096]. Podocin forms homo-oligomers through both its amino- and carboxy-terminal cytoplasmic domains and partitions into plasma-membrane lipid raft microdomains, where it directly binds nephrin and recruits it into rafts to support nephrin signaling [PMID:14570703, PMID:15496146]. Through this scaffolding function podocin organizes the slit diaphragm complex, and loss of functional podocin secondarily redistributes nephrin, CD2AP, and alpha-actinin away from the glomerular basement membrane [PMID:15327385]. Podocin matures through the classical exocytic secretory pathway, and the dominant disease mechanism is mistrafficking: most pathogenic missense mutations cause ER retention (e.g. R138Q, P118L) or accumulation in other compartments such as the Golgi (R168H, R291W) or cytoplasmic inclusions (V180M), reducing podocin levels and disrupting nephrin trafficking, with ER-retained mutants associated with earlier disease onset [PMID:14675423, PMID:15496146, PMID:36167728]. The common R229Q variant reduces nephrin binding and is pathogenic only when trans-associated with specific C-terminal (residue 270–351) mutations that exert a dominant-negative effect via altered heterodimerization and mislocalization [PMID:12464671, PMID:24509478]. Podocin transcription is directly controlled in podocytes by WT1, Lmx1b, and USF1 acting on its promoter [PMID:25556170, PMID:16900088, PMID:19562271].","teleology":[{"year":2000,"claim":"Established the gene underlying autosomal recessive steroid-resistant nephrotic syndrome, defining podocin as a podocyte-specific stomatin-family membrane protein and creating the molecular entry point for slit diaphragm biology.","evidence":"Positional cloning with segregating nonsense, frameshift, and missense mutations; expression analysis in fetal and mature glomeruli","pmids":["10742096"],"confidence":"High","gaps":["Molecular function and binding partners not yet defined","Subcellular localization within podocytes not yet resolved"]},{"year":2002,"claim":"Provided in vivo genetic evidence that nephrin and podocin functionally interact, by showing a tri-allelic NPHS1/NPHS2 combination shifts congenital nephrotic syndrome to congenital FSGS.","evidence":"Mutational analysis and genotype-phenotype epistasis in human patient families","pmids":["11854170"],"confidence":"Medium","gaps":["Interaction inferred from genetics, not biochemical reconstitution","Does not localize where the interaction occurs"]},{"year":2002,"claim":"Gave the first biochemical rationale for R229Q as an FSGS susceptibility allele by demonstrating it reduces podocin-nephrin binding.","evidence":"In vitro translation of podocin and pulldown with purified nephrin","pmids":["12464671"],"confidence":"Medium","gaps":["Single in vitro method, single lab","Does not explain conditional pathogenicity later shown to depend on trans alleles"]},{"year":2003,"claim":"Defined podocin's molecular mechanism: homo-oligomerization and recruitment of nephrin into lipid rafts to enable nephrin signaling, and showed how distinct mutations fail at different steps.","evidence":"Lipid raft fractionation, co-IP, confocal microscopy, and mutagenesis in transfected cell lines","pmids":["14570703"],"confidence":"High","gaps":["Raft recruitment shown in cell lines, not native podocytes","Nature of nephrin signaling augmented by podocin not detailed"]},{"year":2004,"claim":"Established that podocin matures via the classical secretory pathway and that mistrafficking is the unifying disease mechanism, with a genotype-phenotype link between ER retention and earlier onset.","evidence":"Brefeldin A treatment, confocal microscopy and fractionation across 12 disease mutations with clinical correlation","pmids":["14675423"],"confidence":"High","gaps":["Trafficking quality-control machinery handling mutants not identified","Why one mutant routes to late endosomes vs ER unexplained"]},{"year":2004,"claim":"Linked specific C-terminal missense mutants to distinct mislocalization patterns and showed mistrafficked podocin drags nephrin away from the membrane via direct binding.","evidence":"Site-directed mutagenesis, confocal, co-IP and pulldown in HEK293 cells","pmids":["15496146"],"confidence":"High","gaps":["Structural basis of differential mislocalization not resolved","Done in heterologous cells rather than podocytes"]},{"year":2004,"claim":"Confirmed in patient tissue that podocin defects secondarily disorganize the slit diaphragm complex, supporting podocin's scaffolding role for nephrin, CD2AP and alpha-actinin.","evidence":"Immunohistochemistry and in situ hybridization on patient renal biopsies with defined NPHS2 mutations","pmids":["15327385"],"confidence":"Medium","gaps":["Correlative biopsy data, single lab","Direct CD2AP/alpha-actinin binding not biochemically demonstrated here"]},{"year":2006,"claim":"Identified functional promoter polymorphisms that downregulate NPHS2 and named USF1 as a trans-acting factor controlling its expression.","evidence":"Reporter transfection in podocytes, EMSA, and USF1 RNAi silencing","pmids":["16900088"],"confidence":"Medium","gaps":["USF1 contribution in vivo not tested","Single lab"]},{"year":2009,"claim":"Showed Lmx1b acts as a transcriptional enhancer of NPHS2 via a FLAT-F promoter element, extending the regulatory network.","evidence":"Reporter constructs and EMSA in podocytes","pmids":["19562271"],"confidence":"Medium","gaps":["In vivo requirement for the FLAT-F element not established","Two methods, single lab"]},{"year":2014,"claim":"Resolved the conditional pathogenicity of R229Q by showing it causes disease only in trans with specific 3' mutations that act dominant-negatively through altered heterodimerization and mislocalization.","evidence":"Clinical genetics in large cohort plus heterodimerization assays, localization studies and structural modeling","pmids":["24509478"],"confidence":"High","gaps":["Structural detail of the altered heterodimer interface not fully defined","Boundary of pathogenic 3' mutation set may be incomplete"]},{"year":2015,"claim":"Placed NPHS2 in the podocyte transcriptional program as a direct WT1 target, connecting it to master podocyte gene regulation.","evidence":"ChIP-seq with transcriptomics in Nphs2-Cre conditional WT1 knockout mice and zebrafish functional validation","pmids":["25556170"],"confidence":"High","gaps":["Interplay of WT1 with USF1/Lmx1b at the locus not integrated","Direct enhancer occupancy element not mapped here"]},{"year":2016,"claim":"Provided a candidate dominant disease allele, a truncating mutation producing podocin that still binds nephrin yet is associated with fragmented nephrin and reduced podocin in vivo.","evidence":"Co-IP, immunohistochemistry, and whole genome/direct sequencing in a single family","pmids":["27573339"],"confidence":"Medium","gaps":["Single Co-IP, single family","Dominant mechanism not reconstituted experimentally"]},{"year":2022,"claim":"Demonstrated in a human podocyte organoid system that endogenous NPHS2 variants cause variant-specific mistrafficking (ER vs Golgi), reduced podocin protein, impaired nephrin trafficking, and podocyte apoptosis independent of ER stress.","evidence":"iPSC-derived kidney organoids with endogenous patient variants, immunofluorescence, transcriptional profiling, and nephrin-podocin colocalization assays","pmids":["36167728"],"confidence":"High","gaps":["Apoptosis trigger downstream of mistrafficking not identified","Mechanism of protein reduction without transcriptional loss unresolved"]},{"year":null,"claim":"How mistrafficked podocin triggers podocyte death and how the WT1/Lmx1b/USF1 regulatory inputs are integrated at the NPHS2 locus remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined cell-death pathway linking podocin mislocalization to apoptosis","Quality-control machinery degrading mutant podocin not identified","Combined regulation by WT1, Lmx1b and USF1 not modeled together"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,4,10]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,8,9]}],"complexes":["slit diaphragm"],"partners":["NPHS1","CD2AP","ACTN4","WT1","LMX1B","USF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NP85","full_name":"Podocin","aliases":[],"length_aa":383,"mass_kda":42.2,"function":"Plays a role in the regulation of glomerular permeability, acting probably as a linker between the plasma membrane and the cytoskeleton","subcellular_location":"Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q9NP85/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPHS2","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPHS2","total_profiled":1310},"omim":[{"mim_id":"614748","title":"EPIDERMOLYSIS BULLOSA, JUNCTIONAL 7, WITH INTERSTITIAL LUNG DISEASE AND NEPHROTIC SYNDROME; JEB7","url":"https://www.omim.org/entry/614748"},{"mim_id":"610725","title":"NEPHROTIC SYNDROME, TYPE 3; NPHS3","url":"https://www.omim.org/entry/610725"},{"mim_id":"607762","title":"KIRRE-LIKE NEPHRIN FAMILY ADHESION MOLECULE 2; KIRREL2","url":"https://www.omim.org/entry/607762"},{"mim_id":"607761","title":"KIRRE-LIKE NEPHRIN FAMILY ADHESION MOLECULE 3; KIRREL3","url":"https://www.omim.org/entry/607761"},{"mim_id":"607614","title":"NUCLEOPORIN, 160-KD; NUP160","url":"https://www.omim.org/entry/607614"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"kidney","ntpm":244.9}],"url":"https://www.proteinatlas.org/search/NPHS2"},"hgnc":{"alias_symbol":["SRN1","PDCN"],"prev_symbol":[]},"alphafold":{"accession":"Q9NP85","domains":[{"cath_id":"-","chopping":"110-167","consensus_level":"high","plddt":84.2571,"start":110,"end":167},{"cath_id":"3.30.479.30","chopping":"170-271","consensus_level":"high","plddt":94.4734,"start":170,"end":271}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP85","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP85-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NP85-F1-predicted_aligned_error_v6.png","plddt_mean":74.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPHS2","jax_strain_url":"https://www.jax.org/strain/search?query=NPHS2"},"sequence":{"accession":"Q9NP85","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NP85.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NP85/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NP85"}},"corpus_meta":[{"pmid":"10742096","id":"PMC_10742096","title":"NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10742096","citation_count":1102,"is_preprint":false},{"pmid":"17371932","id":"PMC_17371932","title":"Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).","date":"2007","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/17371932","citation_count":316,"is_preprint":false},{"pmid":"14978175","id":"PMC_14978175","title":"Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome.","date":"2004","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/14978175","citation_count":292,"is_preprint":false},{"pmid":"15253708","id":"PMC_15253708","title":"NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.","date":"2004","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15253708","citation_count":263,"is_preprint":false},{"pmid":"14570703","id":"PMC_14570703","title":"Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14570703","citation_count":209,"is_preprint":false},{"pmid":"12464671","id":"PMC_12464671","title":"NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele.","date":"2002","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12464671","citation_count":201,"is_preprint":false},{"pmid":"11854170","id":"PMC_11854170","title":"Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11854170","citation_count":200,"is_preprint":false},{"pmid":"11805166","id":"PMC_11805166","title":"Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome.","date":"2002","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/11805166","citation_count":177,"is_preprint":false},{"pmid":"24509478","id":"PMC_24509478","title":"Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome.","date":"2014","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24509478","citation_count":122,"is_preprint":false},{"pmid":"19145239","id":"PMC_19145239","title":"Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant.","date":"2009","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/19145239","citation_count":104,"is_preprint":false},{"pmid":"8589695","id":"PMC_8589695","title":"Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis.","date":"1995","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8589695","citation_count":100,"is_preprint":false},{"pmid":"11805168","id":"PMC_11805168","title":"Mutations in NPHS2 encoding podocin are a prevalent cause of steroid-resistant nephrotic syndrome among Israeli-Arab children.","date":"2002","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/11805168","citation_count":83,"is_preprint":false},{"pmid":"16481888","id":"PMC_16481888","title":"NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.","date":"2006","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16481888","citation_count":80,"is_preprint":false},{"pmid":"14675423","id":"PMC_14675423","title":"Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations.","date":"2004","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/14675423","citation_count":76,"is_preprint":false},{"pmid":"14871423","id":"PMC_14871423","title":"NPHS2 R229Q functional variant is associated with microalbuminuria in the general population.","date":"2004","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/14871423","citation_count":73,"is_preprint":false},{"pmid":"15817495","id":"PMC_15817495","title":"NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms.","date":"2005","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/15817495","citation_count":72,"is_preprint":false},{"pmid":"24227627","id":"PMC_24227627","title":"NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum.","date":"2013","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/24227627","citation_count":68,"is_preprint":false},{"pmid":"15780077","id":"PMC_15780077","title":"Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome.","date":"2005","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15780077","citation_count":63,"is_preprint":false},{"pmid":"15496146","id":"PMC_15496146","title":"Disease-causing missense mutations in NPHS2 gene alter normal nephrin trafficking to the plasma membrane.","date":"2004","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15496146","citation_count":61,"is_preprint":false},{"pmid":"25556170","id":"PMC_25556170","title":"Integration of Cistromic and Transcriptomic Analyses Identifies Nphs2, Mafb, and Magi2 as Wilms' Tumor 1 Target Genes in Podocyte Differentiation and Maintenance.","date":"2015","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/25556170","citation_count":55,"is_preprint":false},{"pmid":"20947785","id":"PMC_20947785","title":"Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome.","date":"2010","source":"Clinical journal of the American Society of Nephrology : CJASN","url":"https://pubmed.ncbi.nlm.nih.gov/20947785","citation_count":54,"is_preprint":false},{"pmid":"12687458","id":"PMC_12687458","title":"NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children.","date":"2003","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/12687458","citation_count":50,"is_preprint":false},{"pmid":"17699384","id":"PMC_17699384","title":"Recessive NPHS2 (Podocin) mutations are rare in adult-onset idiopathic focal segmental glomerulosclerosis.","date":"2006","source":"Clinical journal of the American Society of Nephrology : CJASN","url":"https://pubmed.ncbi.nlm.nih.gov/17699384","citation_count":49,"is_preprint":false},{"pmid":"18823551","id":"PMC_18823551","title":"NPHS2 variation in focal and segmental glomerulosclerosis.","date":"2008","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/18823551","citation_count":47,"is_preprint":false},{"pmid":"15769810","id":"PMC_15769810","title":"Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children.","date":"2005","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/15769810","citation_count":47,"is_preprint":false},{"pmid":"22228437","id":"PMC_22228437","title":"Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria.","date":"2012","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/22228437","citation_count":46,"is_preprint":false},{"pmid":"17942957","id":"PMC_17942957","title":"NPHS2 variation in sporadic focal segmental glomerulosclerosis.","date":"2007","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/17942957","citation_count":45,"is_preprint":false},{"pmid":"17899208","id":"PMC_17899208","title":"NPHS2 (podicin) mutations in Turkish children with idiopathic nephrotic syndrome.","date":"2007","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/17899208","citation_count":45,"is_preprint":false},{"pmid":"1588964","id":"PMC_1588964","title":"SRN1, a yeast gene involved in RNA processing, is identical to HEX2/REG1, a negative regulator in glucose repression.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1588964","citation_count":44,"is_preprint":false},{"pmid":"18726620","id":"PMC_18726620","title":"The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy.","date":"2008","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/18726620","citation_count":44,"is_preprint":false},{"pmid":"18543005","id":"PMC_18543005","title":"Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome.","date":"2008","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/18543005","citation_count":42,"is_preprint":false},{"pmid":"17934764","id":"PMC_17934764","title":"WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome.","date":"2007","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/17934764","citation_count":42,"is_preprint":false},{"pmid":"15338398","id":"PMC_15338398","title":"No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations.","date":"2004","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/15338398","citation_count":39,"is_preprint":false},{"pmid":"22565185","id":"PMC_22565185","title":"A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan.","date":"2012","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/22565185","citation_count":36,"is_preprint":false},{"pmid":"15327385","id":"PMC_15327385","title":"In vivo expression of podocyte slit diaphragm-associated proteins in nephrotic patients with NPHS2 mutation.","date":"2004","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15327385","citation_count":34,"is_preprint":false},{"pmid":"19406966","id":"PMC_19406966","title":"Clinical features and long-term outcome of nephrotic syndrome associated with heterozygous NPHS1 and NPHS2 mutations.","date":"2009","source":"Clinical journal of the American Society of Nephrology : CJASN","url":"https://pubmed.ncbi.nlm.nih.gov/19406966","citation_count":34,"is_preprint":false},{"pmid":"15015071","id":"PMC_15015071","title":"NPHS2 mutation associated with recurrence of proteinuria after transplantation.","date":"2004","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/15015071","citation_count":33,"is_preprint":false},{"pmid":"28701039","id":"PMC_28701039","title":"Aminofutalosine Synthase: Evidence for Captodative and Aryl Radical Intermediates Using β-Scission and SRN1 Trapping Reactions.","date":"2017","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/28701039","citation_count":32,"is_preprint":false},{"pmid":"15954915","id":"PMC_15954915","title":"Identification of podocin (NPHS2) gene mutations in African Americans with nondiabetic end-stage renal disease.","date":"2005","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/15954915","citation_count":31,"is_preprint":false},{"pmid":"17211152","id":"PMC_17211152","title":"NPHS1 and NPHS2 gene mutations in Chinese children with sporadic nephrotic syndrome.","date":"2007","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/17211152","citation_count":28,"is_preprint":false},{"pmid":"30260545","id":"PMC_30260545","title":"The mutation-dependent pathogenicity of NPHS2 p.R229Q: A guide for clinical assessment.","date":"2018","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/30260545","citation_count":25,"is_preprint":false},{"pmid":"19495806","id":"PMC_19495806","title":"Partial remission with cyclosporine A in a patient with nephrotic syndrome due to NPHS2 mutation.","date":"2009","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/19495806","citation_count":25,"is_preprint":false},{"pmid":"15627790","id":"PMC_15627790","title":"Molecular analysis of NPHS2 and ACTN4 genes in a series of 33 Italian patients affected by adult-onset nonfamilial focal segmental glomerulosclerosis.","date":"2004","source":"Nephron. Clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/15627790","citation_count":24,"is_preprint":false},{"pmid":"17109732","id":"PMC_17109732","title":"Recurrent nephrotic syndrome in homozygous truncating NPHS2 mutation is not due to anti-podocin antibodies.","date":"2006","source":"American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons","url":"https://pubmed.ncbi.nlm.nih.gov/17109732","citation_count":24,"is_preprint":false},{"pmid":"36167728","id":"PMC_36167728","title":"Kidney Organoids Generated Using an Allelic Series of NPHS2 Point Variants Reveal Distinct Intracellular Podocin Mistrafficking.","date":"2022","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/36167728","citation_count":23,"is_preprint":false},{"pmid":"22080622","id":"PMC_22080622","title":"NPHS2 mutations in Indian children with sporadic early steroid resistant nephrotic syndrome.","date":"2011","source":"Indian pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/22080622","citation_count":22,"is_preprint":false},{"pmid":"16721582","id":"PMC_16721582","title":"Recurrence of proteinuria 10 years post-transplant in NPHS2-associated focal segmental glomerulosclerosis after conversion from cyclosporin A to sirolimus.","date":"2006","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16721582","citation_count":21,"is_preprint":false},{"pmid":"23242530","id":"PMC_23242530","title":"NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome.","date":"2012","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/23242530","citation_count":20,"is_preprint":false},{"pmid":"23800802","id":"PMC_23800802","title":"NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis.","date":"2013","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/23800802","citation_count":20,"is_preprint":false},{"pmid":"16810518","id":"PMC_16810518","title":"Analysis of NPHS2 mutations in Turkish steroid-resistant nephrotic syndrome patients.","date":"2006","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16810518","citation_count":18,"is_preprint":false},{"pmid":"26420286","id":"PMC_26420286","title":"NPHS2 mutations account for only 15% of nephrotic syndrome cases.","date":"2015","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26420286","citation_count":17,"is_preprint":false},{"pmid":"19371226","id":"PMC_19371226","title":"Nucleotide variations in the NPHS2 gene in Greek children with steroid-resistant nephrotic syndrome.","date":"2009","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/19371226","citation_count":16,"is_preprint":false},{"pmid":"16874699","id":"PMC_16874699","title":"NPHS2 mutations in adult patients with primary focal segmental glomerulosclerosis.","date":"2006","source":"Journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/16874699","citation_count":16,"is_preprint":false},{"pmid":"16900088","id":"PMC_16900088","title":"Cis and trans regulatory elements in NPHS2 promoter: implications in proteinuria and progression of renal diseases.","date":"2006","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/16900088","citation_count":15,"is_preprint":false},{"pmid":"19395786","id":"PMC_19395786","title":"NPHS2 mutations in children with steroid-resistant nephrotic syndrome.","date":"2009","source":"Iranian journal of kidney diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19395786","citation_count":14,"is_preprint":false},{"pmid":"24856380","id":"PMC_24856380","title":"Retrospective mutational analysis of NPHS1, NPHS2, WT1 and LAMB2 in children with steroid-resistant focal segmental glomerulosclerosis - a single-centre experience.","date":"2014","source":"Bosnian journal of basic medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24856380","citation_count":13,"is_preprint":false},{"pmid":"27885584","id":"PMC_27885584","title":"WT1 and NPHS2 gene mutation analysis and clinical management of steroid-resistant nephrotic syndrome.","date":"2016","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27885584","citation_count":11,"is_preprint":false},{"pmid":"16572591","id":"PMC_16572591","title":"Rare functional variants of podocin (NPHS2) promoter in patients with nephrotic syndrome.","date":"2006","source":"Gene expression","url":"https://pubmed.ncbi.nlm.nih.gov/16572591","citation_count":11,"is_preprint":false},{"pmid":"30241959","id":"PMC_30241959","title":"Nephrotic Syndrome With Mutations in NPHS2: The Role of R229Q and Implications for Genetic Counseling.","date":"2018","source":"American journal of kidney diseases : the official journal of the National Kidney Foundation","url":"https://pubmed.ncbi.nlm.nih.gov/30241959","citation_count":11,"is_preprint":false},{"pmid":"22578956","id":"PMC_22578956","title":"Mutational analysis of the NPHS2 gene in Czech patients with idiopathic nephrotic syndrome.","date":"2012","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/22578956","citation_count":11,"is_preprint":false},{"pmid":"24674236","id":"PMC_24674236","title":"NPHS2 mutation analysis and primary nephrotic syndrome in southern Indians.","date":"2014","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/24674236","citation_count":10,"is_preprint":false},{"pmid":"24072147","id":"PMC_24072147","title":"NPHS2 gene in steroid-resistant nephrotic syndrome: prevalence, clinical course, and mutational spectrum in South-West Iranian children.","date":"2013","source":"Iranian journal of kidney diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24072147","citation_count":10,"is_preprint":false},{"pmid":"20001346","id":"PMC_20001346","title":"A novel mutation in NPHS2 gene identified in a Chinese pedigree with autosomal recessive steroid-resistant nephrotic syndrome.","date":"2009","source":"Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20001346","citation_count":10,"is_preprint":false},{"pmid":"18000687","id":"PMC_18000687","title":"Clinical course and NPHS2 analysis in patients with late steroid-resistant nephrotic syndrome.","date":"2007","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/18000687","citation_count":9,"is_preprint":false},{"pmid":"30013592","id":"PMC_30013592","title":"Screening of the LAMB2, WT1, NPHS1, and NPHS2 Genes in Pediatric Nephrotic Syndrome.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30013592","citation_count":9,"is_preprint":false},{"pmid":"24072153","id":"PMC_24072153","title":"R229Q polymorphism of NPHS2 gene in patients with late-onset steroid-resistance nephrotic syndrome: a preliminary study.","date":"2013","source":"Iranian journal of kidney diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24072153","citation_count":9,"is_preprint":false},{"pmid":"19562271","id":"PMC_19562271","title":"The transcriptional regulation of podocin (NPHS2) by Lmx1b and a promoter single nucleotide polymorphism.","date":"2009","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/19562271","citation_count":9,"is_preprint":false},{"pmid":"18334793","id":"PMC_18334793","title":"NPHS2 mutations.","date":"2008","source":"Indian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/18334793","citation_count":8,"is_preprint":false},{"pmid":"35278126","id":"PMC_35278126","title":"Spectrum of NPHS1 and NPHS2 variants in egyptian children with focal segmental glomerular sclerosis: identification of six novel variants and founder effect.","date":"2022","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/35278126","citation_count":8,"is_preprint":false},{"pmid":"27573339","id":"PMC_27573339","title":"Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern.","date":"2016","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/27573339","citation_count":8,"is_preprint":false},{"pmid":"12608558","id":"PMC_12608558","title":"WT-1 and NPHS2 mutation analysis in patients with non-familial steroid-resistant focal-segmental glomerulosclerosis.","date":"2003","source":"Clinical nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/12608558","citation_count":7,"is_preprint":false},{"pmid":"26820844","id":"PMC_26820844","title":"Report of novel genetic variation in NPHS2 gene associated with idiopathic nephrotic syndrome in South Indian children.","date":"2016","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/26820844","citation_count":7,"is_preprint":false},{"pmid":"24715228","id":"PMC_24715228","title":"The p.R229Q variant of the NPHS2 (podocin) gene in focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome: a meta-analysis.","date":"2014","source":"International urology and nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/24715228","citation_count":6,"is_preprint":false},{"pmid":"15322893","id":"PMC_15322893","title":"A novel mutation of NPHS2 identified in a Chinese family.","date":"2004","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/15322893","citation_count":6,"is_preprint":false},{"pmid":"32129207","id":"PMC_32129207","title":"NPHS2 gene mutations in azerbaijani children with steroid-resistant nephrotic syndrome.","date":"2020","source":"Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia","url":"https://pubmed.ncbi.nlm.nih.gov/32129207","citation_count":5,"is_preprint":false},{"pmid":"23913389","id":"PMC_23913389","title":"Mutations in NPHS2 (podocin) in Mexican children with nephrotic syndrome who respond to standard steroid treatment.","date":"2013","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/23913389","citation_count":5,"is_preprint":false},{"pmid":"24519673","id":"PMC_24519673","title":"NPHS2 R229Q polymorphism in steroid resistant nephrotic syndrome: is it responsive to immunosuppressive therapy?","date":"2014","source":"Journal of tropical pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24519673","citation_count":5,"is_preprint":false},{"pmid":"23468032","id":"PMC_23468032","title":"Familial focal segmental glomerulosclerosis (FSGS) in a Nigerian family and exclusion of mutations in NPHS2,WT1 and APOL1.","date":"2012","source":"West African journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23468032","citation_count":5,"is_preprint":false},{"pmid":"25599733","id":"PMC_25599733","title":"Association between NPHS1 and NPHS2 gene variants and nephrotic syndrome in children.","date":"2015","source":"Iranian journal of kidney diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25599733","citation_count":4,"is_preprint":false},{"pmid":"38765578","id":"PMC_38765578","title":"Steroid-Resistant Nephrotic Syndrome due to NPHS2 Variants Is Not Associated With Posttransplant Recurrence.","date":"2024","source":"Kidney international reports","url":"https://pubmed.ncbi.nlm.nih.gov/38765578","citation_count":4,"is_preprint":false},{"pmid":"28529802","id":"PMC_28529802","title":"R229Q Polymorphism of NPHS2 Gene in Group of Iraqi Children with Steroid-Resistant Nephrotic Syndrome.","date":"2017","source":"International journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/28529802","citation_count":4,"is_preprint":false},{"pmid":"28712774","id":"PMC_28712774","title":"Characterization of NPHS2 gene polymorphisms associated to steroid resistance nephrotic syndrome in Indian children.","date":"2017","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/28712774","citation_count":4,"is_preprint":false},{"pmid":"24089165","id":"PMC_24089165","title":"CD80, suPAR and nephrotic syndrome in a case of NPHS2 mutation.","date":"2013","source":"Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia","url":"https://pubmed.ncbi.nlm.nih.gov/24089165","citation_count":4,"is_preprint":false},{"pmid":"15504144","id":"PMC_15504144","title":"A novel NPHS2 gene mutation in Turkish children with familial steroid-resistant nephrotic syndrome.","date":"2004","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/15504144","citation_count":4,"is_preprint":false},{"pmid":"21171529","id":"PMC_21171529","title":"Plasmapheresis-induced clinical improvement in a patient with steroid-resistant nephrotic syndrome due to podocin (NPHS2) gene mutation.","date":"2010","source":"Acta medica (Hradec Kralove)","url":"https://pubmed.ncbi.nlm.nih.gov/21171529","citation_count":4,"is_preprint":false},{"pmid":"25852895","id":"PMC_25852895","title":"Steroid-resistant nephrotic syndrome with mutations in NPHS2 (podocin): report from a three-generation family.","date":"2014","source":"Clinical kidney journal","url":"https://pubmed.ncbi.nlm.nih.gov/25852895","citation_count":4,"is_preprint":false},{"pmid":"33305316","id":"PMC_33305316","title":"NPHS2 gene polymorphism aggravates renal damage caused by focal segmental glomerulosclerosis with COL4A3 mutation.","date":"2021","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/33305316","citation_count":3,"is_preprint":false},{"pmid":"28785586","id":"PMC_28785586","title":"NPHS2 Mutations: A Closer Look to Latin American Countries.","date":"2017","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/28785586","citation_count":3,"is_preprint":false},{"pmid":"22120861","id":"PMC_22120861","title":"Foothold of NPHS2 mutations in primary nephrotic syndrome.","date":"2011","source":"Journal of postgraduate medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22120861","citation_count":3,"is_preprint":false},{"pmid":"20025681","id":"PMC_20025681","title":"Genetic effect of the NPHS2 gene variants on proteinuria in minimal change disease and immunoglobulin A nephropathy.","date":"2009","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/20025681","citation_count":3,"is_preprint":false},{"pmid":"32585588","id":"PMC_32585588","title":"Generation of an induced pluripotent stem cell (iPSC) line (IMAGINi007) from a patient with steroid-resistant nephrotic syndrome carrying the homozygous p.R138Q mutation in the podocin-encoding NPHS2 gene.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32585588","citation_count":3,"is_preprint":false},{"pmid":"29663071","id":"PMC_29663071","title":"Cyclosporine A responsive congenital nephrotic syndrome with single heterozygous variants in NPHS1, NPHS2, and PLCE1.","date":"2018","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/29663071","citation_count":3,"is_preprint":false},{"pmid":"25949463","id":"PMC_25949463","title":"A novel mutation in NPHS2 causing nephrotic syndrome in a Saudi Arabian family.","date":"2010","source":"NDT plus","url":"https://pubmed.ncbi.nlm.nih.gov/25949463","citation_count":3,"is_preprint":false},{"pmid":"37322227","id":"PMC_37322227","title":"NPHS2-6 drives cervical squamous cell carcinoma (CSCC) progression via hsa-miR-1323/SMC1B axis to activate PI3K-Akt pathway.","date":"2023","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/37322227","citation_count":2,"is_preprint":false},{"pmid":"31949506","id":"PMC_31949506","title":"Analysis of NPHS2 Gene Mutations in Egyptian Children with Nephrotic Syndrome.","date":"2019","source":"Open access Macedonian journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31949506","citation_count":2,"is_preprint":false},{"pmid":"38170106","id":"PMC_38170106","title":"The most common founder pathogenic variant c.868G > A (p.Val290Met) in the NPHS2 gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood.","date":"2023","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38170106","citation_count":2,"is_preprint":false},{"pmid":"33428103","id":"PMC_33428103","title":"Analysis of the clinical characteristics of arthritis with renal disease caused by a NPHS2 gene mutation.","date":"2021","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/33428103","citation_count":2,"is_preprint":false},{"pmid":"26455708","id":"PMC_26455708","title":"[NPHS2 Mutation analysis study in children with steroid-resistant nephrotic syndrome].","date":"2015","source":"Revista chilena de pediatria","url":"https://pubmed.ncbi.nlm.nih.gov/26455708","citation_count":2,"is_preprint":false},{"pmid":"32482922","id":"PMC_32482922","title":"CG/CA genotypes represent novel markers in the NPHS2 gene region associated with nephrotic syndrome.","date":"2020","source":"Journal of genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32482922","citation_count":2,"is_preprint":false},{"pmid":"25112471","id":"PMC_25112471","title":"NPHS2 variation in Chinese southern infants with late steroid-resistant nephrotic syndrome.","date":"2014","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/25112471","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50475,"output_tokens":3293,"usd":0.10041,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10895,"output_tokens":3847,"usd":0.075325,"stage2_stop_reason":"end_turn"},"total_usd":0.175735,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"NPHS2 encodes podocin, a novel integral membrane protein belonging to the stomatin protein family, almost exclusively expressed in podocytes of fetal and mature kidney glomeruli, identified by positional cloning as the causative gene for autosomal recessive steroid-resistant nephrotic syndrome.\",\n      \"method\": \"Positional cloning, sequence analysis, expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — positional cloning with multiple independent mutations (nonsense, frameshift, missense) segregating with disease; foundational discovery replicated across many subsequent studies\",\n      \"pmids\": [\"10742096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Wild-type podocin forms homo-oligomers involving both carboxy and amino terminal cytoplasmic domains, and is targeted to plasma membrane lipid raft microdomains where it recruits nephrin into rafts. Disease-causing mutations R138Q and R138X fail to recruit nephrin into rafts: R138Q is retained in the endoplasmic reticulum, while R138X reaches the plasma membrane but fails to associate with rafts. Neither mutant augments nephrin signaling.\",\n      \"method\": \"Confocal microscopy, lipid raft fractionation, co-immunoprecipitation, site-directed mutagenesis, transfection in cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, co-IP, confocal imaging, mutagenesis) in single rigorous study; findings on ER retention replicated by multiple subsequent labs\",\n      \"pmids\": [\"14570703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Podocin biosynthesis follows the classical secretory (exocytic) pathway through the endoplasmic reticulum (demonstrated by brefeldin A treatment causing ER accumulation). Of 12 disease-causing NPHS2 mutations tested, 9 mutants failed to reach the plasma membrane: 8 were retained in the ER and 1 localized to late endosomes. Mutants retained in the ER are associated with earlier disease onset than those correctly targeted to the membrane.\",\n      \"method\": \"Brefeldin A treatment, confocal microscopy, subcellular fractionation, transfection in cell lines, genotype-phenotype correlation\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mutations tested with orthogonal methods (brefeldin A, confocal, fractionation); ER retention finding replicated independently\",\n      \"pmids\": [\"14675423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The R229Q variant of podocin shows decreased binding to nephrin in vitro, providing a molecular mechanism by which this common polymorphism contributes to FSGS susceptibility.\",\n      \"method\": \"In vitro translation of podocin, pulldown assay with purified nephrin\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct binding assay with in vitro-translated proteins, single lab, single method\",\n      \"pmids\": [\"12464671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense mutations in the proximal C-terminus of podocin (R138Q, V180M, R291W) cause aberrant subcellular localization: R138Q is retained in the ER, V180M forms cytoplasmic inclusion bodies, and R291W is trapped in the ER and small intracellular vesicles. This abnormal podocin localization also alters nephrin trafficking to the plasma membrane in cotransfected cells, due to direct protein-protein binding between podocin and nephrin.\",\n      \"method\": \"Site-directed mutagenesis, confocal microscopy, immunoprecipitation, pulldown assay, transfection in HEK293 cells\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (confocal, co-IP, pulldown, mutagenesis); findings on podocin-nephrin interaction and ER retention independently replicated\",\n      \"pmids\": [\"15496146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In vivo, NPHS2 mutations cause profound alteration of podocin expression and/or subcellular distribution in patient kidney biopsies. Secondary changes in distribution of nephrin, CD2AP, and alpha-actinin occur in association with podocin defects, with these proteins redistributed from the glomerular basement membrane to the podocyte body, supporting a scaffolding role for podocin in organization of the slit diaphragm.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization, renal biopsy analysis of patients with defined NPHS2 mutations\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct patient biopsy analysis with multiple slit diaphragm markers, multiple mutation types, single lab\",\n      \"pmids\": [\"15327385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The pathogenicity of NPHS2 p.R229Q is mutation-dependent: it causes disease only when trans-associated with specific 3' NPHS2 mutations (affecting residues 270–351). These 3' mutations exert a dominant-negative effect on p.R229Q podocin through altered heterodimerization and mislocalization of the p.R229Q podocin, but behave as recessive alleles when associated with wild-type podocin.\",\n      \"method\": \"Clinical genetic analysis, protein heterodimerization assays, subcellular localization studies, structural modeling\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (heterodimerization assay, localization, genotype-phenotype in large cohort, structural analysis); published in Nature Genetics with rigorous evidence\",\n      \"pmids\": [\"24509478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Nphs2 (podocin) is a direct transcriptional target of the Wilms' tumor suppressor WT1 in podocytes, identified by integration of chromatin immunoprecipitation sequencing (ChIP-seq) with transcriptomic analysis in WT1 knockout models, and functionally validated in zebrafish.\",\n      \"method\": \"ChIP-seq, cDNA microarray, Nphs2-Cre conditional WT1 knockout mice, zebrafish functional assays\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-seq plus transcriptomics plus in vivo KO model plus zebrafish validation; multiple orthogonal methods across species\",\n      \"pmids\": [\"25556170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Three functional promoter polymorphisms of NPHS2 (-51T, -116T, and -535 insCTTTTTT3) cause strong downregulation of reporter gene expression in podocytes. Electrophoretic mobility shift assays showed that wild-type variants form specific DNA-protein complexes with podocyte nuclear extracts abolished by the rare forms. USF1 was identified as the specific trans-acting factor binding the -51G site, confirmed by binding inhibition and USF1 RNAi silencing.\",\n      \"method\": \"Reporter gene transfection in podocytes, EMSA, RNAi silencing of USF1, haplotype analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus EMSA plus RNAi in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16900088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The transcription factor Lmx1b regulates podocin (NPHS2) transcription by binding to a FLAT-F element in the promoter, demonstrating enhancer function. The SNP variant -116T in the promoter causes significant reduction in luciferase activity with altered nuclear protein binding.\",\n      \"method\": \"Reporter gene constructs, gel shift (EMSA) analysis, transfection in podocytes\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus EMSA in podocytes, single lab, two orthogonal methods\",\n      \"pmids\": [\"19562271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In kidney organoids derived from iPSCs bearing endogenous NPHS2 pathogenic missense variants, distinct variants cause unique patterns of PODOCIN subcellular mistrafficking: P118L and R138Q are preferentially retained in the ER; R168H and R291W accumulate in the Golgi. All variants result in reduced PODOCIN protein levels without reduced transcription, variant-specific effects on NEPHRIN-PODOCIN colocalization and NEPHRIN trafficking, and podocyte-specific apoptosis not linked to ER stress.\",\n      \"method\": \"iPSC-derived kidney organoids, immunofluorescence, transcriptional profiling, PODOCIN-NEPHRIN colocalization assays, patient-derived iPSC lines\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous variants in physiologically relevant human podocyte organoid system, multiple variants with orthogonal methods (IF, transcriptomics, colocalization), patient-derived validation\",\n      \"pmids\": [\"36167728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A heterozygous truncating mutation in NPHS2 (c.988_989delCT) causing dominant-pattern familial SRNS produces a truncated podocin that retains the ability to bind nephrin (by co-immunoprecipitation), but is associated with fragmented nephrin expression and reduced podocin expression in vivo.\",\n      \"method\": \"Co-immunoprecipitation, immunohistochemistry, whole genome sequencing, direct sequencing\",\n      \"journal\": \"Clinical and experimental nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP experiment in single lab, limited mechanistic follow-up, single family\",\n      \"pmids\": [\"27573339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Genetic epistasis between NPHS1 and NPHS2 was demonstrated: a 'tri-allelic' combination of NPHS1 and NPHS2 mutations modifies the phenotype from congenital nephrotic syndrome to congenital FSGS, providing functional evidence for a direct interaction between nephrin and podocin in the glomerular filtration barrier.\",\n      \"method\": \"Mutational analysis, genotype-phenotype epistasis in human patients\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic epistasis analysis across multiple families, replicated in subsequent studies; mechanism inferred from genotype-phenotype rather than biochemical reconstitution\",\n      \"pmids\": [\"11854170\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPHS2 encodes podocin, a stomatin-family integral membrane protein exclusively expressed in kidney podocytes, where it localizes to plasma membrane lipid raft microdomains at the slit diaphragm via the classical secretory pathway; podocin forms homo-oligomers and recruits nephrin into lipid rafts to facilitate nephrin signaling, while also scaffolding CD2AP and alpha-actinin at the slit diaphragm; most disease-causing mutations cause ER retention or mistargeting of podocin which secondarily mislocalizes nephrin and disrupts the slit diaphragm complex; podocin expression is transcriptionally regulated by WT1 and Lmx1b; and the pathogenicity of the common R229Q variant is mutation-dependent, causing disease only when trans-associated with specific C-terminal mutations through altered heterodimerization and mislocalization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPHS2 encodes podocin, a stomatin-family integral membrane protein almost exclusively expressed in kidney glomerular podocytes, where it was identified by positional cloning as the causative gene for autosomal recessive steroid-resistant nephrotic syndrome [#0]. Podocin forms homo-oligomers through both its amino- and carboxy-terminal cytoplasmic domains and partitions into plasma-membrane lipid raft microdomains, where it directly binds nephrin and recruits it into rafts to support nephrin signaling [#1, #4]. Through this scaffolding function podocin organizes the slit diaphragm complex, and loss of functional podocin secondarily redistributes nephrin, CD2AP, and alpha-actinin away from the glomerular basement membrane [#5]. Podocin matures through the classical exocytic secretory pathway, and the dominant disease mechanism is mistrafficking: most pathogenic missense mutations cause ER retention (e.g. R138Q, P118L) or accumulation in other compartments such as the Golgi (R168H, R291W) or cytoplasmic inclusions (V180M), reducing podocin levels and disrupting nephrin trafficking, with ER-retained mutants associated with earlier disease onset [#2, #4, #10]. The common R229Q variant reduces nephrin binding and is pathogenic only when trans-associated with specific C-terminal (residue 270–351) mutations that exert a dominant-negative effect via altered heterodimerization and mislocalization [#3, #6]. Podocin transcription is directly controlled in podocytes by WT1, Lmx1b, and USF1 acting on its promoter [#7, #8, #9].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the gene underlying autosomal recessive steroid-resistant nephrotic syndrome, defining podocin as a podocyte-specific stomatin-family membrane protein and creating the molecular entry point for slit diaphragm biology.\",\n      \"evidence\": \"Positional cloning with segregating nonsense, frameshift, and missense mutations; expression analysis in fetal and mature glomeruli\",\n      \"pmids\": [\"10742096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular function and binding partners not yet defined\", \"Subcellular localization within podocytes not yet resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Provided in vivo genetic evidence that nephrin and podocin functionally interact, by showing a tri-allelic NPHS1/NPHS2 combination shifts congenital nephrotic syndrome to congenital FSGS.\",\n      \"evidence\": \"Mutational analysis and genotype-phenotype epistasis in human patient families\",\n      \"pmids\": [\"11854170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction inferred from genetics, not biochemical reconstitution\", \"Does not localize where the interaction occurs\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Gave the first biochemical rationale for R229Q as an FSGS susceptibility allele by demonstrating it reduces podocin-nephrin binding.\",\n      \"evidence\": \"In vitro translation of podocin and pulldown with purified nephrin\",\n      \"pmids\": [\"12464671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro method, single lab\", \"Does not explain conditional pathogenicity later shown to depend on trans alleles\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined podocin's molecular mechanism: homo-oligomerization and recruitment of nephrin into lipid rafts to enable nephrin signaling, and showed how distinct mutations fail at different steps.\",\n      \"evidence\": \"Lipid raft fractionation, co-IP, confocal microscopy, and mutagenesis in transfected cell lines\",\n      \"pmids\": [\"14570703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Raft recruitment shown in cell lines, not native podocytes\", \"Nature of nephrin signaling augmented by podocin not detailed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that podocin matures via the classical secretory pathway and that mistrafficking is the unifying disease mechanism, with a genotype-phenotype link between ER retention and earlier onset.\",\n      \"evidence\": \"Brefeldin A treatment, confocal microscopy and fractionation across 12 disease mutations with clinical correlation\",\n      \"pmids\": [\"14675423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking quality-control machinery handling mutants not identified\", \"Why one mutant routes to late endosomes vs ER unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked specific C-terminal missense mutants to distinct mislocalization patterns and showed mistrafficked podocin drags nephrin away from the membrane via direct binding.\",\n      \"evidence\": \"Site-directed mutagenesis, confocal, co-IP and pulldown in HEK293 cells\",\n      \"pmids\": [\"15496146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of differential mislocalization not resolved\", \"Done in heterologous cells rather than podocytes\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Confirmed in patient tissue that podocin defects secondarily disorganize the slit diaphragm complex, supporting podocin's scaffolding role for nephrin, CD2AP and alpha-actinin.\",\n      \"evidence\": \"Immunohistochemistry and in situ hybridization on patient renal biopsies with defined NPHS2 mutations\",\n      \"pmids\": [\"15327385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative biopsy data, single lab\", \"Direct CD2AP/alpha-actinin binding not biochemically demonstrated here\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified functional promoter polymorphisms that downregulate NPHS2 and named USF1 as a trans-acting factor controlling its expression.\",\n      \"evidence\": \"Reporter transfection in podocytes, EMSA, and USF1 RNAi silencing\",\n      \"pmids\": [\"16900088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"USF1 contribution in vivo not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed Lmx1b acts as a transcriptional enhancer of NPHS2 via a FLAT-F promoter element, extending the regulatory network.\",\n      \"evidence\": \"Reporter constructs and EMSA in podocytes\",\n      \"pmids\": [\"19562271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo requirement for the FLAT-F element not established\", \"Two methods, single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the conditional pathogenicity of R229Q by showing it causes disease only in trans with specific 3' mutations that act dominant-negatively through altered heterodimerization and mislocalization.\",\n      \"evidence\": \"Clinical genetics in large cohort plus heterodimerization assays, localization studies and structural modeling\",\n      \"pmids\": [\"24509478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the altered heterodimer interface not fully defined\", \"Boundary of pathogenic 3' mutation set may be incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed NPHS2 in the podocyte transcriptional program as a direct WT1 target, connecting it to master podocyte gene regulation.\",\n      \"evidence\": \"ChIP-seq with transcriptomics in Nphs2-Cre conditional WT1 knockout mice and zebrafish functional validation\",\n      \"pmids\": [\"25556170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay of WT1 with USF1/Lmx1b at the locus not integrated\", \"Direct enhancer occupancy element not mapped here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided a candidate dominant disease allele, a truncating mutation producing podocin that still binds nephrin yet is associated with fragmented nephrin and reduced podocin in vivo.\",\n      \"evidence\": \"Co-IP, immunohistochemistry, and whole genome/direct sequencing in a single family\",\n      \"pmids\": [\"27573339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP, single family\", \"Dominant mechanism not reconstituted experimentally\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated in a human podocyte organoid system that endogenous NPHS2 variants cause variant-specific mistrafficking (ER vs Golgi), reduced podocin protein, impaired nephrin trafficking, and podocyte apoptosis independent of ER stress.\",\n      \"evidence\": \"iPSC-derived kidney organoids with endogenous patient variants, immunofluorescence, transcriptional profiling, and nephrin-podocin colocalization assays\",\n      \"pmids\": [\"36167728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apoptosis trigger downstream of mistrafficking not identified\", \"Mechanism of protein reduction without transcriptional loss unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How mistrafficked podocin triggers podocyte death and how the WT1/Lmx1b/USF1 regulatory inputs are integrated at the NPHS2 locus remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No defined cell-death pathway linking podocin mislocalization to apoptosis\", \"Quality-control machinery degrading mutant podocin not identified\", \"Combined regulation by WT1, Lmx1b and USF1 not modeled together\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 4, 10]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 8, 9]}\n    ],\n    \"complexes\": [\"slit diaphragm\"],\n    \"partners\": [\"NPHS1\", \"CD2AP\", \"ACTN4\", \"WT1\", \"LMX1B\", \"USF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}