Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Modeling of ACTN4-based podocytopathy using Drosophila nephrocytes

[thumbnail of Original Article]
Preview
PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
3MB
[thumbnail of Supplementary Material]
Preview
PDF (Supplementary Material) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
315kB

Item Type:Article
Title:Modeling of ACTN4-based podocytopathy using Drosophila nephrocytes
Creators Name:Odenthal, J., Dittrich, S., Ludwig, V., Merz, T., Reitmeier, K., Reusch, B., Höhne, M., Cosgun, Z.C., Hohenadel, M., Putnik, J., Göbel, H., Rinschen, M.M., Altmüller, J., Koehler, S., Schermer, B., Benzing, T., Beck, B.B., Brinkkötter, P.T., Habbig, S. and Bartram, M.P.
Abstract:INTRODUCTION: Genetic disorders are among the most prevalent causes leading to progressive glomerular disease and, ultimately, end-stage renal disease in children and adolescents. Identification of underlying genetic causes is indispensable for targeted treatment strategies and counseling of affected patients and their families. METHODS: Here, we report a boy who presented at four years of age with proteinuria and biopsy-proven focal segmental glomerulosclerosis that was temporarily responsive to treatment with Ciclosporin A. Molecular genetic testing identified a novel mutation in alpha-actinin-4 (p.M240T). We describe a feasible and efficient experimental approach to test its pathogenicity by combining in silico, in vitro, and in vivo analyses. RESULTS: The de novo p.M240T mutation led to decreased alpha-Actinin-4 stability as well as protein mislocalization and actin cytoskeleton rearrangements. Transgenic expression of wild-type human alpha-Actinin-4 in Drosophila melanogaster nephrocytes was able to ameliorate phenotypes associated with the knockdown of endogenous Actinin. In contrast, p.M240T, as well as other established disease variants p.W59R and p.K255E, failed to rescue these phenotypes, underlining the pathogenicity of the novel alpha-Actinin-4 variant. CONCLUSION: Our data highligh that the newly identified alpha-actinin-4 mutation indeed encodes for a disease-causing variant of the protein and promote the Drosophila model as a simple and convenient tool to study monogenic kidney disease in vivo.
Keywords:ACTN4, FSGS, Nephrocyte, Nephrotic Syndrome, Podocyte, Animals, Drosophila
Source:Kidney International Reports
ISSN:2468-0249
Publisher:Elsevier
Volume:8
Number:2
Page Range:317-329
Date:February 2023
Official Publication:https://doi.org/10.1016/j.ekir.2022.10.024
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library