Universität zu Köln

Odenthal, Johanna, Dittrich, Sebastian, Ludwig, Vivian, Merz, Tim, Reitmeier, Katrin, Reusch, Bjoern, Hoehne, Martin, Cosgun, Zuelfue C., Hohenadel, Maximilian, Putnik, Jovana, Goebel, Heike, Rinschen, Markus M., Altmueller, Janine, Koehler, Sybille, Schermer, Bernhard, Benzing, Thomas ORCID: 0000-0003-0512-1066, Beck, Bodo B., Brinkkoetter, Paul T., Habbig, Sandra and Bartram, Malte P. (2022). Modeling of ACTN4-Based Podocytopathy Using Drosophila Nephrocytes. Kidney Int. Rep., 8 (2). S. 317 - 330. NEW YORK: ELSEVIER SCIENCE INC. ISSN 2468-0249

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Abstract

Introduction: Genetic disorders are among the most prevalent causes leading to progressive glomerular disease and, ultimately, end-stage renal disease (ESRD) 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 on a boy who presented at 4 years of age with proteinuria and biopsy-proven focal segmental glomerulosclerosis (FSGS) that was temporarily responsive to treatment with ciclo-sporin 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 highlight 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Odenthal, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Dittrich, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, Vivian UNSPECIFIED UNSPECIFIED UNSPECIFIED Merz, Tim UNSPECIFIED UNSPECIFIED UNSPECIFIED Reitmeier, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Reusch, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Cosgun, Zuelfue C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hohenadel, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Putnik, Jovana UNSPECIFIED UNSPECIFIED UNSPECIFIED Goebel, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Rinschen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Sybille UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED orcid.org/0000-0003-0512-1066 UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brinkkoetter, Paul T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Habbig, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Bartram, Malte P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691114
DOI:	10.1016/j.ekir.2022.10.024
Journal or Publication Title:	Kidney Int. Rep.
Volume:	8
Number:	2
Page Range:	S. 317 - 330
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	2468-0249
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACTIN-BINDING DOMAIN; ALPHA-ACTININ; PROTEIN STABILITY; CRYSTAL-STRUCTURE; NEPHROTIC SYNDROME; GENOME SEQUENCE; VERSATILE MODEL; ALPHA-ACTININ-4; CELL; DISEASE Multiple languages Urology & Nephrology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69111