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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,21]]},"abstract":"<jats:p>\n                    The most frequent causative genes in podocytopathies are\n                    <jats:italic toggle=\"yes\">NPHS1<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">NPHS2<\/jats:italic>\n                    that encode the main slit diaphragm components nephrin and podocin, respectively. The significance of the nephrin\u2013podocin interaction has remained elusive. The\n                    <jats:italic toggle=\"yes\">NPHS2<\/jats:italic>\n                    R229Q variant is unique in human genetics as it is only pathogenic when\n                    <jats:italic toggle=\"yes\">trans<\/jats:italic>\n                    -associated to specific 3\u2019 variants causing R229Q podocin to form distorted heterooligomers. To examine the effect of podocin on the distance between nephrin molecules, nephrin constructs labeled with YPet or mCherry\/mRuby were transitionally coexpressed in HEK-293 cells. We assessed the nephrin\u2013nephrin distance based on the F\u00f6rster Resonance Energy Transfer (FRET) efficiency between YPet and mCherry\/mRuby in living cells. Podocin markedly increased the FRET efficiency between nephrin molecules, reflecting reduced and ordered nephrin\u2013nephrin distances. Its effect was abolished by pathogenic podocin variants. Pathogenic R229Q heterooligomers exhibited increased FRET efficiency between their PHB domains that correlated with a larger nephrin\u2013nephrin distance, thereby explaining the associated mild phenotype. The effect of pathogenic and benign R229Q heterooligomers separated sharply in their effect on nephrin\u2013nephrin spacing (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 1.19E-33). Based on an intermediate effect on the nephrin\u2013nephrin distance and five families with late-onset FSGS, we reconsider the R229Q-R286Tfs*17 association as pathogenic, but via a mechanism different from other R229Q associations and with incomplete penetrance. In conclusion, podocin provides regularly spaced intracellular anchor points for nephrin chains. Podocin homo-oligomerization affects the nephrin\u2013nephrin spacing, thereby providing an explanation for albuminuria in patients with podocin dysfunction and for the interallelic interactions of R229Q.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2524893123","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T18:02:21Z","timestamp":1776189741000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Podocin oligomers regulate the ordering of nephrin chains, providing the molecular basis of\n                    <i>NPHS2<\/i>\n                    interallelic interactions"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8658-6329","authenticated-orcid":false,"given":"Violetta","family":"Antal-K\u00f3nya","sequence":"first","affiliation":[{"name":"Magyar Tudom\u00e1nyos Akad\u00e9mia-Semmelweis Egyetem Lend\u00fclet Nephrogenetic 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Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Balogh","sequence":"additional","affiliation":[{"name":"Magyar Tudom\u00e1nyos Akad\u00e9mia-Semmelweis Egyetem Lend\u00fclet Nephrogenetic Laboratory","place":["Budapest, Hungary"]},{"name":"Semmelweis University, Pediatric Center, MTA Center of Excellence","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"Mik\u00f3","sequence":"additional","affiliation":[{"name":"Magyar Tudom\u00e1nyos Akad\u00e9mia-Semmelweis Egyetem Lend\u00fclet Nephrogenetic Laboratory","place":["Budapest, Hungary"]},{"name":"Semmelweis University, Pediatric Center, MTA Center of Excellence","place":["Budapest, Hungary"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e1niel","family":"Seidl","sequence":"additional","affiliation":[{"name":"Magyar Tudom\u00e1nyos Akad\u00e9mia-Semmelweis Egyetem Lend\u00fclet Nephrogenetic 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