Frontiers in Cell and Developmental Biology (Aug 2020)
SLC20A1 Is Involved in Urinary Tract and Urorectal Development
- Johanna Magdalena Rieke,
- Johanna Magdalena Rieke,
- Johanna Magdalena Rieke,
- Rong Zhang,
- Doreen Braun,
- Öznur Yilmaz,
- Anna S. Japp,
- Anna S. Japp,
- Filipa M. Lopes,
- Michael Pleschka,
- Michael Pleschka,
- Alina C. Hilger,
- Alina C. Hilger,
- Sophia Schneider,
- Sophia Schneider,
- William G. Newman,
- Glenda M. Beaman,
- Agneta Nordenskjöld,
- Agneta Nordenskjöld,
- Anne-Karoline Ebert,
- Martin Promm,
- Wolfgang H. Rösch,
- Raimund Stein,
- Karin Hirsch,
- Frank-Mattias Schäfer,
- Eberhard Schmiedeke,
- Thomas M. Boemers,
- Martin Lacher,
- Dietrich Kluth,
- Jan-Hendrik Gosemann,
- Magnus Anderberg,
- Gillian Barker,
- Gundela Holmdahl,
- Göran Läckgren,
- David Keene,
- Raimondo M. Cervellione,
- Elisa Giorgio,
- Elisa Giorgio,
- Massimo Di Grazia,
- Wouter F. J. Feitz,
- Carlo L. M. Marcelis,
- Iris A. L. M. Van Rooij,
- Arend Bökenkamp,
- Goedele M. A. Beckers,
- Catherine E. Keegan,
- Catherine E. Keegan,
- Amit Sharma,
- Amit Sharma,
- Tikam Chand Dakal,
- Lars Wittler,
- Phillip Grote,
- Nadine Zwink,
- Ekkehart Jenetzky,
- Ekkehart Jenetzky,
- Alfredo Brusco,
- Alfredo Brusco,
- Holger Thiele,
- Michael Ludwig,
- Ulrich Schweizer,
- Adrian S. Woolf,
- Adrian S. Woolf,
- Benjamin Odermatt,
- Benjamin Odermatt,
- Heiko Reutter,
- Heiko Reutter
Affiliations
- Johanna Magdalena Rieke
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Johanna Magdalena Rieke
- Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Johanna Magdalena Rieke
- Department of Pediatrics, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, Germany
- Rong Zhang
- Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
- Doreen Braun
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Öznur Yilmaz
- Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Anna S. Japp
- Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany
- Anna S. Japp
- Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany
- Filipa M. Lopes
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
- Michael Pleschka
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Michael Pleschka
- Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Alina C. Hilger
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Alina C. Hilger
- Department of Pediatrics, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, Germany
- Sophia Schneider
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Sophia Schneider
- Department of Neonatology and Pediatric Intensive Care, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, Germany
- William G. Newman
- Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Glenda M. Beaman
- Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Agneta Nordenskjöld
- 0Department of Women’s and Children’s Health, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
- Agneta Nordenskjöld
- 1Pediatric Surgery, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
- Anne-Karoline Ebert
- 2Department of Urology and Pediatric Urology, University Hospital of Ulm, Ulm, Germany
- Martin Promm
- 3Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, Regensburg, Germany
- Wolfgang H. Rösch
- 3Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, Regensburg, Germany
- Raimund Stein
- 4Medical Faculty Mannheim, Centre for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Karin Hirsch
- 5Division of Pediatric Urology, Department of Urology, University of Erlangen-Nürnberg, Erlangen, Germany
- Frank-Mattias Schäfer
- 6Department of Pediatric Surgery and Urology, Cnopfsche Kinderklinik, Nürnberg, Germany
- Eberhard Schmiedeke
- 7Department of Pediatric Surgery and Urology, Center for Child and Youth Health, Klinikum Bremen-Mitte, Bremen, Germany
- Thomas M. Boemers
- 8Department of Pediatric Surgery and Pediatric Urology, Children’s Hospital of Cologne, Cologne, Germany
- Martin Lacher
- 9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Dietrich Kluth
- 9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Jan-Hendrik Gosemann
- 9Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Magnus Anderberg
- 0Department of Pediatric Surgery, Skane University Hospital Lund, Lund, Sweden
- Gillian Barker
- 1Department of Women’s and Children’s Health, Uppsala Academic Children Hospital, Uppsala, Sweden
- Gundela Holmdahl
- 2Department of Pediatric Surgery, Queen Silvias Children’s Hospital, Gothenburg, Sweden
- Göran Läckgren
- 3Pediatric Urology, University Children’s Hospital, Uppsala, Sweden
- David Keene
- 4Pediatric Urology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
- Raimondo M. Cervellione
- 4Pediatric Urology, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom
- Elisa Giorgio
- 5Department of Medical Sciences, University of Torino, Turin, Italy
- Elisa Giorgio
- 6Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy
- Massimo Di Grazia
- 7Pediatric Urology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca’ Granda-Ospedale Maggiore Policlinico, Milan, Italy
- Wouter F. J. Feitz
- 8Division of Pediatric Urology, Department of Urology, Radboudumc Amalia Children’s Hospital, Nijmegen, Netherlands
- Carlo L. M. Marcelis
- 9Department of Genetics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
- Iris A. L. M. Van Rooij
- 0Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, Netherlands
- Arend Bökenkamp
- 1Emma Children’s Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Goedele M. A. Beckers
- 2Department of Urology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Catherine E. Keegan
- 3Division of Genetics, Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States
- Catherine E. Keegan
- 4Department of Human Genetics, University of Michigan, Ann Arbor, MI, United States
- Amit Sharma
- 5Department of Neurology, University Hospital Bonn, Bonn, Germany
- Amit Sharma
- 6Department of Ophthalmology, University Hospital Bonn, Bonn, Germany
- Tikam Chand Dakal
- 7Department of Biotechnology, Mohanlal Sukhadia University Udaipur, Udaipur, India
- Lars Wittler
- 8Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany
- Phillip Grote
- 9Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, Frankfurt am Main, Germany
- Nadine Zwink
- 0Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
- Ekkehart Jenetzky
- 0Department of Pediatric and Adolescent Psychiatry and Psychotherapy, University Medical Centre, Johannes Gutenberg University of Mainz, Mainz, Germany
- Ekkehart Jenetzky
- 1Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany
- Alfredo Brusco
- 5Department of Medical Sciences, University of Torino, Turin, Italy
- Alfredo Brusco
- 6Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy
- Holger Thiele
- 2Cologne Center for Genomics, University of Cologne, Cologne, Germany
- Michael Ludwig
- 3Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
- Ulrich Schweizer
- Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
- Adrian S. Woolf
- Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology Medicine and Health, School of Biological Sciences, University of Manchester, Manchester, United Kingdom
- Adrian S. Woolf
- 4Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom
- Benjamin Odermatt
- Institute for Anatomy and Cell Biology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Benjamin Odermatt
- 5Institute for Neuroanatomy, University Hospital Bonn, University of Bonn, Bonn, Germany
- Heiko Reutter
- Institute of Human Genetics, University Hospital Bonn, Bonn, Germany
- Heiko Reutter
- Department of Neonatology and Pediatric Intensive Care, Children’s Hospital Medical Center, University Hospital Bonn, Bonn, Germany
- DOI
- https://doi.org/10.3389/fcell.2020.00567
- Journal volume & issue
-
Vol. 8
Abstract
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Keywords
- SLC20A1
- urinary tract development
- kidney formation
- zebrafish development
- cloacal malformation
- functional genetics
