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

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dc.contributor.authorRiedhammer, K.M.
dc.contributor.authorNguyen, T.-M.T.
dc.contributor.authorKoşukcu, C.
dc.contributor.authorCalzada-Wack, J.
dc.contributor.authorLi, Y.
dc.contributor.authorAssia, Batzir, N.
dc.contributor.authorSaygılı S.
dc.date.accessioned2024-05-19T14:33:33Z
dc.date.available2024-05-19T14:33:33Z
dc.date.issued2024
dc.departmentİstinye Üniversitesien_US
dc.description.abstractCongenital 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 knockout 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 knockout 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 toward a stromal cell identity. Histology of Foxd2 knockout 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. © 2023 International Society of Nephrologyen_US
dc.description.sponsorshipRijksuniversiteit Groningen, RUG; Deutsche Forschungsgemeinschaft, DFG; Technische Universität München, TUM; Universiteit Utrecht, UU; National Institutes of Health, NIH: DK068306; National Institutes of Health, NIH; Bundesministerium für Bildung und Forschung, BMBF: BE 3910/8-1, BE 3910/9-1, 01KX1012, 431984000, 01GM1903G, 01GM1903I; Bundesministerium für Bildung und Forschung, BMBF; 01EE2303E; European Research Council, ERC: 716344, 431984000 – SFB 1453, 503306912 – FOR 5547, 499552394 – SFB 1597; European Research Council, ERC; EXC-2189, 523737608 – SCHL 2292/2-1, 390939984; National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK: U24DK114886, U01DK133092, U01DK114933, U01DK114920, U01DK133095, U01DK133768, U01DK133113, U01DK114908, U01DK114907, U01DK133090, U01DK133097, U01DK133766, U01DK133091, U01DK114866, U01DK133081, U01DK133093, U01DK114923; National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK; Istanbul Üniversitesi-Cerrahpasa, IÜC: TOA-2021-35349, 274036608 - HO 2583/8-3; Istanbul Üniversitesi-Cerrahpasa, IÜCen_US
dc.description.sponsorshipWe thank the index individuals and their families for participation in the study and S. Potter for the kind gift of mk4 cells. We further thank Simone Sanna-Cherchi (Department of Medicine, Division of Nephrology, Columbia University, New York, New York, USA), Nine Knoers (Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands), and Kirsten Renkema (Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands) for kindly searching their next-generation sequencing databases for cases with FOXD2 variants. We also thank Lily Bazak (Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel) for technical assistance with variant interpretation in family 3. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) and the Technical University of Munich in the framework of the Open Access Publishing Program and by the Scientific Research Projects Coordination Unit of Istanbul University – Cerrahpasa (No.: TOA-2021-35349). JH received funding from the DFG (project ID 274036608 - HO 2583/8-3). MS acknowledges funding via the Radboudumc Hypatia Tenure Track grant, the European Research Council (ERC) starting grant TREATCilia (grant agreement no. 716344), and the DFG (project ID 499552394 – SFB 1597 and project ID 503306912 – FOR 5547). YL, SH, MW, PS, CB, C. Schell, MS, AK, and SJA acknowledge funding from the DFG (project ID 431984000 – SFB 1453). MS, AK, and SA acknowledge funding additionally from the Excellence Initiative Centre for Integrative Biological Signalling Studies (CIBSS) (EXC-2189) (project ID 390939984). PS was supported by the DFG (project ID 523737608 – SCHL 2292/2-1). The German Mouse Clinic was supported by the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012 to MHdA) and German Center for Diabetes Research (DZD; to MHdA). CB holds a part-time faculty appointment at the University of Freiburg in addition to his engagement with the Medizinische Genetik Mainz and his employment with the Limbach Group for which he heads and manages Limbach Genetics GmbH. His laboratories receive support from the DFG (BE 3910/8-1 and BE 3910/9-1), Collaborative Research Center (SFB) 1453 (project ID 431984000), and the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]; 01GM1903I and 01GM1903G). FH was supported by a grant from the National Institutes of Health (grant no. DK068306). WW was supported by the BMBF and the Bavarian State Ministry of Science and the Arts within the initial phase of the German Center for Mental Health (Deutsches Zentrum für Psychische Gesundheit [DZPG]; grant no. 01EE2303E). The Kidney Precision Medicine Project is funded by the following grants from the National Institute of Diabetes and Digestive and Kidney Diseases: U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, and U24DK114886. Participants whose pedigree data are presented in this manuscript gave consent to publish the family history in pedigree or summarized format.en_US
dc.description.sponsorshipThis work was supported by the German Research Foundation ( Deutsche Forschungsgemeinschaft [DFG]) and the Technical University of Munich in the framework of the Open Access Publishing Program and by the Scientific Research Projects Coordination Unit of Istanbul University – Cerrahpasa (No.: TOA-2021-35349). JH received funding from the DFG (project ID 274036608 - HO 2583/8-3). MS acknowledges funding via the Radboudumc Hypatia Tenure Track grant, the European Research Council (ERC) starting grant TREATCilia (grant agreement no. 716344), and the DFG (project ID 499552394 – SFB 1597 and project ID 503306912 – FOR 5547). YL, SH, MW, PS, CB, C. Schell, MS, AK, and SJA acknowledge funding from the DFG (project ID 431984000 – SFB 1453). MS, AK, and SA acknowledge funding additionally from the Excellence Initiative Centre for Integrative Biological Signalling Studies (CIBSS) (EXC-2189) (project ID 390939984). PS was supported by the DFG (project ID 523737608 – SCHL 2292/2-1). The German Mouse Clinic was supported by the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012 to MHdA) and German Center for Diabetes Research (DZD; to MHdA). CB holds a part-time faculty appointment at the University of Freiburg in addition to his engagement with the Medizinische Genetik Mainz and his employment with the Limbach Group for which he heads and manages Limbach Genetics GmbH. His laboratories receive support from the DFG (BE 3910/8-1 and BE 3910/9-1), Collaborative Research Center (SFB) 1453 (project ID 431984000), and the Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF]; 01GM1903I and 01GM1903G). FH was supported by a grant from the National Institutes of Health (grant no. DK068306). WW was supported by the BMBF and the Bavarian State Ministry of Science and the Arts within the initial phase of the German Center for Mental Health (Deutsches Zentrum für Psychische Gesundheit [DZPG]; grant no. 01EE2303E).en_US
dc.description.sponsorshipThe Kidney Precision Medicine Project is funded by the following grants from the National Institute of Diabetes and Digestive and Kidney Diseases : U01DK133081, U01DK133091, U01DK133092, U01DK133093, U01DK133095, U01DK133097, U01DK114866, U01DK114908, U01DK133090, U01DK133113, U01DK133766, U01DK133768, U01DK114907, U01DK114920, U01DK114923, U01DK114933, and U24DK114886.en_US
dc.identifier.doi10.1016/j.kint.2023.11.032
dc.identifier.endpage864en_US
dc.identifier.issn0085-2538
dc.identifier.issue4en_US
dc.identifier.pmid38154558en_US
dc.identifier.scopus2-s2.0-85187518559en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage844en_US
dc.identifier.urihttps://doi.org/10.1016/j.kint.2023.11.032
dc.identifier.urihttps://hdl.handle.net/20.500.12713/4267
dc.identifier.volume105en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevier B.V.en_US
dc.relation.ispartofKidney Internationalen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.snmz20240519_kaen_US
dc.subjectCakuten_US
dc.subjectChronic Kidney Diseaseen_US
dc.subjectFoxd2en_US
dc.subjectPax2en_US
dc.subjectRenal Hypoplasiaen_US
dc.subjectUrinary Albumin-To-Creatinine Ratio (Uacr)en_US
dc.subjectWnt4en_US
dc.titleImplication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT)en_US
dc.typeArticleen_US

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