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)–induced 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’s autosomal dominant inheritance.

中文翻译：

---

INF2 突变通过功能获得机制导致肾脏疾病


倒置的福尔辛-2 （INF2） 突变的杂合性导致局灶节段性肾小球硬化 （FSGS），伴或不伴 Charcot-Marie-Tooth 病。一个关键问题是该疾病是由 INF2 的功能获得效应还是功能丧失（单倍体不足）引起的。尽管在多个细胞过程中已确定作用，但 INF2 敲除小鼠和具有疾病相关点突变的小鼠均未表现出明显的肾脏或神经表型。在这里，我们比较了 INF2 R218Q 和 INF2 敲除小鼠对嘌呤霉素氨基核苷 （PAN） 诱导的肾损伤的反应。与 INF2 敲除小鼠相比，R218Q INF2 小鼠易患肾小球疾病。共定位、免疫共沉淀分析和细胞肌动蛋白测量表明，INF2 R218Q 对肌动蛋白细胞骨架具有功能获得效应。RNA 表达分析显示，粘附和线粒体相关通路在 PAN 处理的 R218Q 小鼠中富集。来自 INF2 R218Q 小鼠和具有 INF2 突变 （S186P） 的人肾类器官的足细胞都概括了粘附和线粒体表型。因此，功能获得机制驱动 INF2 相关 FSGS 并解释该疾病的常染色体显性遗传。