| Item | Evidence summary | Key source (authors/year) | URL/DOI |
|---|---|---|---|
| Molecular identity & domains/topology | NPHS2 encodes podocin, corresponding to UniProt Q9NP85/Q9NP85_PODO_HUMAN; podocin is a PHB/band7-SPFH/stomatin-like family protein with a hairpin-like membrane topology and both N- and C-termini facing the cytoplasm (pqac-00000002, pqac-00000003, pqac-00000007, pqac-00000010, pqac-00000011) | Schurek et al. 2014; Huber et al. 2003; Butt et al. 2023 | https://doi.org/10.1074/jbc.m113.521773; https://doi.org/10.1093/hmg/ddg360; https://doi.org/10.1186/s12882-023-03420-x |
| Molecular identity & domains/topology | A conserved proline preceding the PHB domain helps maintain podocin’s monotopic hairpin topology; disease-causing proline mutation P118L/P120L can flip topology toward a transmembrane form, expose the C-terminus extracellularly, and permit N-glycosylation (pqac-00000001, pqac-00000008, pqac-00000009) | Schurek et al. 2014 | https://doi.org/10.1074/jbc.m113.521773 |
| Subcellular localization | Podocin localizes to the podocyte slit diaphragm and to detergent-resistant/lipid-raft membrane microdomains, where it is enriched with nephrin and other slit diaphragm proteins (pqac-00000002, pqac-00000008, pqac-00000010, pqac-00000011) | Huber et al. 2003; Schurek et al. 2014 | https://doi.org/10.1093/hmg/ddg360; https://doi.org/10.1074/jbc.m113.521773 |
| Subcellular localization | STED microscopy in the 2023 Δexon5 model showed wild-type podocin at the slit diaphragm, whereas homozygous Δexon5 animals lacked slit-diaphragm podocin and had severely disrupted foot process morphology; the short isoform was retained around the ER in cells (pqac-00000030, pqac-00000031, pqac-00000044) | Butt et al. 2023 | https://doi.org/10.1186/s12882-023-03420-x |
| Core molecular functions | Podocin acts primarily as a scaffolding/organizing protein rather than an enzyme or transporter: it oligomerizes and recruits nephrin into lipid-raft microdomains required for nephrin signaling at the slit diaphragm (pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000037, pqac-00000040) | Huber et al. 2003 | https://doi.org/10.1093/hmg/ddg360 |
| Core molecular functions | Podocin binds cholesterol and partitions into detergent-resistant membranes; correct membrane topology is required for cholesterol interaction and slit-diaphragm microdomain organization (pqac-00000008, pqac-00000009, pqac-00000014) | Schurek et al. 2014; Butt et al. 2023 | https://doi.org/10.1074/jbc.m113.521773; https://doi.org/10.1186/s12882-023-03420-x |
| Core molecular functions | Podocin modulates ion channel signaling: wild-type podocin augments TRPC6 currents, whereas topology-disrupting P118L/P3L mutants lose this activity (pqac-00000008, pqac-00000009) | Schurek et al. 2014 | https://doi.org/10.1074/jbc.m113.521773 |
| Key interaction partners | Experimentally supported partners include nephrin, CD2AP, TRPC6, and NEPH1/Neph1; podocin also forms homo-oligomers/multimers and megadalton supercomplexes via the PHB domain (pqac-00000008, pqac-00000010, pqac-00000011, pqac-00000015) | Huber et al. 2003; Schurek et al. 2014; Rinschen et al. 2016 | https://doi.org/10.1093/hmg/ddg360; https://doi.org/10.1074/jbc.m113.521773; https://doi.org/10.1093/hmg/ddw016 |
| Key interaction partners | Reviews interpret podocin as a lipid-raft adaptor/coupling component of the slit-diaphragm signaling hub that links membrane complexes to the actin cytoskeleton together with nephrin and CD2AP (pqac-00000038, pqac-00000039, pqac-00000042) | Ha 2013; Welsh & Saleem 2010 | https://doi.org/10.5527/wjn.v2.i1.1; https://doi.org/10.1002/path.2661 |
| Pathogenic mechanisms (mutation effects) | Disease-causing mutants disrupt podocin function by distinct mechanisms: R138Q causes ER retention and failed surface delivery; R138X reaches the surface but fails raft targeting; both lose the ability to recruit nephrin into rafts and augment nephrin signaling (pqac-00000011, pqac-00000012, pqac-00000013, pqac-00000037, pqac-00000041) | Huber et al. 2003 | https://doi.org/10.1093/hmg/ddg360 |
| Pathogenic mechanisms (mutation effects) | Topology-altering proline mutants lose detergent-resistant membrane association, reduce cholesterol binding, and fail to augment TRPC6 currents, linking topology defects directly to podocin dysfunction and disease (pqac-00000008, pqac-00000009) | Schurek et al. 2014 | https://doi.org/10.1074/jbc.m113.521773 |
| Pathogenic mechanisms (mutation effects) | Podocin stability is regulated post-translationally: Ubr4 controls podocin/MEC-2 supercomplex stability, and site-specific ubiquitylation (for example K301) affects stability/unfolding of the PHB domain (pqac-00000015) | Rinschen et al. 2016 | https://doi.org/10.1093/hmg/ddw016 |
| 2023–2024 developments | A short human podocin isoform lacking exon 5 was characterized in vivo; the murine equivalent (Δexon5) caused severe congenital albuminuria, neonatal lethality, markedly reduced podocin protein despite preserved mRNA, absence from the slit diaphragm, and reduced nephrin protein—showing the short isoform cannot substitute for canonical podocin (pqac-00000014, pqac-00000029, pqac-00000030, pqac-00000044) | Butt et al. 2023 | https://doi.org/10.1186/s12882-023-03420-x |
| 2023–2024 developments | A 2024 CNV study of 138 SRNS families identified a causal homozygous exonic NPHS2 deletion (6,790 bp), supporting CNV analysis as an added diagnostic layer beyond SNV-focused sequencing (pqac-00000020) | Pantel et al. 2024 | https://doi.org/10.1007/s00467-023-06134-2 |
| 2023–2024 developments | Urine-derived podocytes from genetically characterized SRNS patients were used as a drug-screening platform; neonatal kidney progenitor cell extracellular vesicles reduced albumin permeability across all tested lines, whereas standard drugs often did not, highlighting a personalized translational model relevant to NPHS2-associated podocytopathy (pqac-00000021) | Tanzi et al. 2024 | https://doi.org/10.1186/s12967-024-05575-z |
| Clinical applications & statistics | In a 2024 systematic review/meta-analysis, 2,889 pediatric patients across 40 studies were screened for NPHS2 variants; pooled NPHS2 mutation prevalence was 11% (95% CI 8–14%; I2 = 73.8%), with reported population ranges of ~10–60% across studies (pqac-00000017, pqac-00000019) | Lee et al. 2024 | https://doi.org/10.3390/ijms252212275 |
| Clinical applications & statistics | Across 18 studies reporting renal outcomes in pediatric NPHS-mutation cohorts, pooled ESRF proportion was 47% (95% CI 34–61%; I2 = 75.4%); Europe-specific analysis suggested higher ESRF risk in NPHS2 carriers (reported OR ~7.97) (pqac-00000017, pqac-00000018) | Lee et al. 2024 | https://doi.org/10.3390/ijms252212275 |
| Clinical applications & statistics | Reviews and meta-analysis recommend NPHS2 testing for earlier diagnosis, family counseling, and to avoid unnecessary steroid/immunosuppressive treatment in monogenic SRNS/FSGS; NGS is advocated for diagnostic workup and family donor screening, and genetic NPHS2 disease is noted to have low post-transplant recurrence relative to primary FSGS (pqac-00000023, pqac-00000025, pqac-00000026, pqac-00000028) | Lee et al. 2024; Mitrotti et al. 2024; Prasad et al. 2024; Bonilla et al. 2024 | https://doi.org/10.3390/ijms252212275; https://doi.org/10.1007/s00467-023-06046-1; https://doi.org/10.1093/ckj/sfae218; https://doi.org/10.1016/j.xkme.2024.100826 |


*Table: This table summarizes verified molecular, mechanistic, translational, and clinical evidence for human NPHS2/podocin (UniProt Q9NP85). It is designed as a compact reference linking each major claim to specific supporting sources and URLs/DOIs.*