Your browser doesn't support javascript.
loading
Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).
Riedhammer, Korbinian M; Nguyen, Thanh-Minh T; Kosukcu, Can; Calzada-Wack, Julia; Li, Yong; Assia Batzir, Nurit; Saygili, Seha; Wimmers, Vera; Kim, Gwang-Jin; Chrysanthou, Marialena; Bakey, Zeineb; Sofrin-Drucker, Efrat; Kraiger, Markus; Sanz-Moreno, Adrián; Amarie, Oana V; Rathkolb, Birgit; Klein-Rodewald, Tanja; Garrett, Lillian; Hölter, Sabine M; Seisenberger, Claudia; Haug, Stefan; Schlosser, Pascal; Marschall, Susan; Wurst, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valerie; Wuttke, Matthias; Hrabe de Angelis, Martin; Comic, Jasmina; Akgün Dogan, Özlem; Özlük, Yasemin; Tasdemir, Mehmet; Agbas, Ayse; Canpolat, Nur; Orenstein, Naama; Çaliskan, Salim; Weber, Ruthild G; Bergmann, Carsten; Jeanpierre, Cecile; Saunier, Sophie; Lim, Tze Y; Hildebrandt, Friedhelm; Alhaddad, Bader; Basel-Salmon, Lina; Borovitz, Yael; Wu, Kaman; Antony, Dinu; Matschkal, Julia; Schaaf, Christian W; Renders, Lutz.
Afiliación
  • Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
  • Nguyen TT; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Kosukcu C; Department of Bioinformatics, Hacettepe University Institute of Health Sciences, Ankara, Türkiye.
  • Calzada-Wack J; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Li Y; Institute of Genetic Epidemiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Assia Batzir N; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
  • Saygili S; Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Türkiye.
  • Wimmers V; Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Kim GJ; Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Germany.
  • Chrysanthou M; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Bakey Z; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Sofrin-Drucker E; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
  • Kraiger M; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Sanz-Moreno A; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Amarie OV; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Rathkolb B; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-University Munich, Munich, Germany; German Center for Di
  • Klein-Rodewald T; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Garrett L; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Hölter SM; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Dev
  • Seisenberger C; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Haug S; Institute of Genetic Epidemiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Schlosser P; Institute of Genetic Epidemiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • Marschall S; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Wurst W; Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Chair of Developmental Genetics, TUM School of Life Sciences (SoLS), Technical University of Munich, Freising, Germany; Deutsches Institut für Neurodegenerative Erkra
  • Fuchs H; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Gailus-Durner V; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
  • Wuttke M; Institute of Genetic Epidemiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Hrabe de Angelis M; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Chair of Experimental Genetics, TUM School of Life Sciences (SoLS), Technical Univ
  • Comic J; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
  • Akgün Dogan Ö; Department of Pediatrics, Division of Pediatric Genetics, Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Türkiye.
  • Özlük Y; Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Türkiye.
  • Tasdemir M; Department of Pediatric Nephrology, Istinye University Faculty of Medicine, Istanbul, Türkiye.
  • Agbas A; Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Türkiye.
  • Canpolat N; Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Türkiye.
  • Orenstein N; Pediatric Genetics Unit, Schneider Children's Medical Center of Israel, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • Çaliskan S; Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, Istanbul, Türkiye.
  • Weber RG; Department of Human Genetics, Hannover Medical School, Hannover, Germany.
  • Bergmann C; Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany; Department of Medicine IV, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Jeanpierre C; Laboratoire des Maladies Rénales Héréditaires, Institut Imagine, Université Paris Cité, INSERM UMR 1163, Paris, France.
  • Saunier S; Laboratoire des Maladies Rénales Héréditaires, Institut Imagine, Université Paris Cité, INSERM UMR 1163, Paris, France.
  • Lim TY; Department of Medicine, Division of Nephrology, Columbia University, New York, New York, USA.
  • Hildebrandt F; Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Alhaddad B; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
  • Basel-Salmon L; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel; Felsenstein Medical Research Center, Petah Tikva, Israel.
  • Borovitz Y; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Institute of Nephrology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
  • Wu K; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • Antony D; Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Center for Pediatrics and Adolescent Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
  • Matschkal J; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
  • Schaaf CW; Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
  • Renders L; Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health, Munich, Germany.
Kidney Int ; 105(4): 844-864, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38154558
ABSTRACT
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 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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Urinario / Anomalías Urogenitales / Reflujo Vesicoureteral / Estructuras Embrionarias / Factores de Transcripción Forkhead / Riñón / Enfermedades Renales / Nefronas Límite: Adult / Animals / Humans Idioma: En Revista: Kidney Int Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Urinario / Anomalías Urogenitales / Reflujo Vesicoureteral / Estructuras Embrionarias / Factores de Transcripción Forkhead / Riñón / Enfermedades Renales / Nefronas Límite: Adult / Animals / Humans Idioma: En Revista: Kidney Int Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos