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Riedhammer, K.M.* ; Nguyen, T.T.* ; Koşukcu, C.* ; Calzada-Wack, J. ; Li, Y.* ; Batzir, N.A.* ; Saygılı, S.* ; Wimmers, V.* ; Kim, G.J.* ; Chrysanthou, M.* ; Bakey, Z.* ; Sofrin-Drucker, E.* ; Kraiger, M. ; Sanz-Moreno, A. ; Amarie, O.V. ; Rathkolb, B. ; Klein-Rodewald, T. ; Garrett, L. ; Hölter, S.M. ; Seisenberger, C. ; Haug, S.* ; Schlosser, P.* ; Marschall, S. ; Wurst, W. ; Fuchs, H. ; Gailus-Durner, V. ; Wuttke, M.* ; Hrabě de Angelis, M. ; Ćomić, J.* ; Doğan, N.* ; Özlük, Y.* ; Taşdemir, M.* ; Ağbaş, A.* ; Canpolat, N.* ; Orenstein, N.* ; Çalışkan, S.* ; Weber, R.G.* ; Bergmann, C.* ; Jeanpierre, C.* ; Saunier, S.* ; Lim, T.Y.* ; Hildebrandt, F.* ; Alhaddad, B.* ; Basel-Salmon, L.* ; Borovitz, Y.* ; Wu, K.* ; Antony, D.* ; Matschkal, J.* ; Schaaf, C.W.* ; Renders, L.* ; Schmaderer, C.* ; Rogg, M.* ; Schell, C.* ; Meitinger, T.* ; Heemann, U.* ; Köttgen, A.* ; Arnold, S.J.* ; Ozaltin, F.* ; Schmidts, M.* ; Hoefele, J.*

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Kidney Int. 105, 844-864 (2023)

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Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knock-out of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift towards a stromal cell identity. Histology of Foxd2 knock-out mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cakut ; Foxd2 ; Pax2 ; Wnt4 ; Albuminuria ; Chronic Kidney Disease ; Renal Hypoplasia; Neural Crest Cells; Epithelial Transformation; Metanephric Mesenchyme; Key Players; Web Server; Gene; Expression; Variants; Mutation; Growth

ISSN (print) / ISBN 0085-2538

e-ISSN 1523-1755

Journal Kidney International

Quellenangaben Volume: 105, Issue: 4, Pages: 844-864

Publisher Nature Publishing Group

Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Experimental Genetics (IEG)
Institute of Developmental Genetics (IDG)

Grants BMBF
National Institutes of Health
Federal Ministry of Education and Research (Bundesministerium fr Bildung und Forschung
Limbach Genetics GmbH
German Center for Diabetes Research
German Federal Ministry of Education and Research
Excellence Initiative Centre for Integrative Biological Signalling Studies (CIBSS)
European Research Council (ERC) starting grant TREATCilia
Radboudumc Hypatia Tenure Track grant
DFG
Scienti fic Research Projects Coordination Unit of Istanbul University
Technical University of Munich
Bavarian State Ministry of Science and the Arts within the initial phase of the German Center for Mental Health (Deutsches Zentrum fr Psychische Gesundheit)
National Institute of Diabetes and Digestive and Kidney Diseases

German Research Foundation (Deutsche Forschungsgemeinschaft