NPHS1 (nephrin, human, O60500) notes

2026-10-21 — Full re-review, independent of the ProtNLM2 predictions

Context: NPHS1 is the closest experimentally characterised relative of DROME/sns
(Q0E9F2). This review treats NPHS1 in its own right; ProtNLM2 output was not
consulted.

Deep research

• just deep-research-falcon human NPHS1 --fallback perplexity-lite failed: falcon
  returned 403 Forbidden at the Edison auth endpoint, and the perplexity-lite
  fallback timed out (600 s). No deep-research file exists; the review is built
  from cached publications, UniProt and Reactome.

Evolutionary placement

• UniProt: PANTHER; PTHR11640:SF136; NEPHRIN. Same subfamily holds fly Sns and
  Hbs and worm SYG-2; the Neph/Kirre partners (KIRREL1-3, fly Kirre/Rst, worm
  SYG-1) are in a different subfamily (SF31), so they are heterophilic partners,
  not orthologs.
• IBA rows (plasma membrane, cell-cell junction, cell adhesion molecule binding,
  cell-cell adhesion) derive from PAINT node PTN002267852; O60500 is itself a donor
  for plasma membrane. PAINT did NOT propagate myoblast fusion from that node even
  though fly Sns/Hbs carry it experimentally - treated as a deliberate decision.
  Human/mouse myoblast-fusion annotations here rest only on mouse Ensembl-Compara
  IEA transfer from the mouse KO study.

Key human / mammalian experimental findings

• Positional cloning; IgSF transmembrane protein; mutated in Finnish congenital
  nephrotic syndrome PMID:9660941.
• Human nephrin localises to the slit diaphragm by immunogold EM
  PMID:10393930; NPHS1 patients
  lack SD PMID:10393930.
• Mouse Nphs1 KO: absent SD, foot process effacement, neonatal death
  PMID:11136707.
• Homophilic adhesion of human nephrin ectodomain (SPR) and cell aggregation
  PMID:14633607.
• Heterophilic: human nephrin binds worm SYG-1 (Neph1 ortholog) and rescues syg-2
  mutants PMID:21858180.
  Reactome curates NPHS1:KIRREL cis heterodimers.
• Phospho-tyrosine signalling: Src-family (Fyn) phosphorylates cytoplasmic YDxV
  motifs that recruit Nck SH2, driving actin assembly
  PMID:16525419;
  PMID:16543952.
• Podocin binds the cytoplasmic tail and enhances nephrin signalling (PMID:11562357).
• Myoblast fusion (zebrafish morphants, mouse KO myoblasts in vitro):
  PMID:19470472.
  Necessity-level evidence only; kept non-core.

Decisions summary

• Core: SD component; homophilic/heterophilic cell adhesion molecule binding;
  slit diaphragm assembly; phospho-tyrosine scaffold (SH2 domain binding) linking
  SD to actin via Nck.
• Generic protein binding: NCK1 row -> SH2 domain binding; SYG-1 row -> cell
  adhesion molecule binding; IQGAP1 row removed as uninformative.
• GBM development (IEP, nephrin used as marker) marked over-annotated; skeletal
  muscle tissue development (organismal phenotype) over-annotated; myoblast
  fusion and synapse protein localisation (heterologous worm rescue) kept non-core.