{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:14:51Z","timestamp":1787159691562,"version":"build-2736575974"},"reference-count":49,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"46","license":[{"start":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T00:00:00Z","timestamp":1731456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.science.org\/content\/page\/science-licenses-journal-article-reuse"}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,11,15]]},"abstract":"<jats:p>Heterozygosity for inverted formin-2 (INF2) mutations causes focal segmental glomerulosclerosis (FSGS) with or without Charcot-Marie-Tooth disease. A key question is whether the disease is caused by gain-of-function effects on INF2 or loss of function (haploinsufficiency). Despite established roles in multiple cellular processes, neither INF2 knockout mice nor mice with a disease-associated point mutation display an evident kidney or neurologic phenotype. Here, we compared responses to puromycin aminonucleoside (PAN)\u2013induced kidney injury between INF2 R218Q and INF2 knockout mice. R218Q INF2 mice are susceptible to glomerular disease, in contrast to INF2 knockout mice. Colocalization, coimmunoprecipitation analyses, and cellular actin measurements showed that INF2 R218Q confers a gain-of-function effect on the actin cytoskeleton. RNA expression analysis showed that adhesion and mitochondria-related pathways were enriched in the PAN-treated R218Q mice. Both podocytes from INF2 R218Q mice and human kidney organoids with an INF2 mutation (S186P) recapitulate adhesion and mitochondrial phenotypes. Thus, gain-of-function mechanisms drive INF2-related FSGS and explain this disease\u2019s autosomal dominant inheritance.<\/jats:p>","DOI":"10.1126\/sciadv.adr1017","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T14:00:02Z","timestamp":1731506402000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":17,"title":["INF2 mutations cause kidney disease through a gain-of-function mechanism"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6807-0257","authenticated-orcid":true,"given":"Balajikarthick","family":"Subramanian","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."},{"name":"Kidney Bioengineering Resource Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0725-8180","authenticated-orcid":true,"given":"Sarah","family":"Williams","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3341-2824","authenticated-orcid":true,"given":"Sophie","family":"Karp","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Flore","family":"Hennino","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 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Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."},{"name":"Kidney Bioengineering Resource Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA."},{"name":"Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 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