ArticleEBioMedicine2014
Human Kidney Disease-causing INF2 Mutations Perturb Rho/Dia Signaling in the Glomerulus.
Article in EBioMedicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 29 citations in OpenAlex.
- Patient-specific hiPSC-Podocytes as an in vitro model of genetic FSGS.Scientific reports · 2025Article
- Regulation of formin INF2 and its alteration in INF2-linked inherited disorders.Cellular and molecular life sciences : CMLS · 2024Review
- INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.Cellular and molecular life sciences : CMLS · 2024Article
- Role of formin INF2 in human diseases.Molecular biology reports · 2022Review
- Role of actin cytoskeleton in podocytes.Pediatric nephrology (Berlin, Germany) · 2021Review
- Dysregulated Dynein-Mediated Trafficking of Nephrin Causes INF2-related Podocytopathy.Journal of the American Society of Nephrology : JASN · 2021Article
- The actin polymerization factor Diaphanous and the actin severing protein Flightless I collaborate to regulate sarcomere size.Developmental biology · 2021Article
- DAAM2 Variants Cause Nephrotic Syndrome via Actin Dysregulation.American journal of human genetics · 2020Article
- The formin INF2 in disease: progress from 10 years of research.Cellular and molecular life sciences : CMLS · 2020Review
- A Deregulated Stress Response Underlies Distinct INF2-Associated Disease Profiles.Journal of the American Society of Nephrology : JASN · 2020Article
- New Paradigm for Cytoskeletal Organization in Podocytes: Proteolytic Fragments of INF2 Formin Function Independently of INF2 Actin Regulatory Activity.Journal of the American Society of Nephrology : JASN · 2020Article
- Mutation of microphthalmia-associated transcription factor (mitf) in zebrafish sensitizes for glomerulopathy.Biology open · 2019Article
- Review
- The Evolving Complexity of the Podocyte Cytoskeleton.Journal of the American Society of Nephrology : JASN · 2017Review
- Inverted formins: A subfamily of atypical formins.Cytoskeleton (Hoboken, N.J.) · 2017Review
- Genetic basis of adult-onset nephrotic syndrome and focal segmental glomerulosclerosis.Frontiers of medicine · 2017Review
- A network of conserved formins, regulated by the guanine exchange factor EXC-5 and the GTPase CDC-42, modulates tubulogenesis in vivo.Development (Cambridge, England) · 2016Article
- Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury.Kidney international · 2016Article
- Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ α-1) and profilin 2.Bioscience reports · 2016Article
- Podocytes.F1000Research · 2016Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations in Inverted Formin 2 (INF2), a diaphanous formin family protein that regulates actin cytoskeleton dynamics, cause focal segmental glomerulosclerosis (FSGS) and Charcot-Marie-Tooth Disease (CMT) in humans. In addition to directly remodeling actin filaments in vitro, we have shown that INF2 regulates intracellular actin dynamics and actin dependent cellular behavior by opposing Rhoa/Dia signaling. As a step towards a better understanding of the human kidney disease, we wanted to explore the relevance of these findings to the in vivo situation. We used dose dependent knockdown of INF2 to first define an in vivo model and establish an overt glomerular phenotype in zebrafish. This simple assay was validated by rescue with wild type INF2 confirming the specificity of the findings. The edema, podocyte dysfunction, and an altered glomerular filtration barrier observed in the zebrafish pronephros correlate with mistrafficking of glomerular slit diaphragm proteins, defective slit-diaphragm signaling, and disinhibited diaphanous formin (mDia) activity. In contrast to wild-type human INF2, INF2 mutants associated with kidney disease fail to rescue the zINF2 morphant phenotype. Of particular interest, this INF2 knockdown phenotype is also rescued by loss of either RhoA or Dia2. This simple assay allows the demonstration that INF2 functions, at least in part, to modulate Dia-mediated Rho signaling, and that disease causing mutations specifically impair this regulatory function. These data support a model in which disease-associated diaphanous inhibitory domain (DID) mutants in INF2 interfere with its binding to and inhibition of Dia, leading to uncontrolled Rho/Dia signaling and perturbed actin dynamics. Methods to fine tune Rho signaling in the glomerulus may lead to new approaches to therapy in humans.
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Registered trials
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