2. Academic Validation
  3. Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction

Rare Variants in BNC2 Are Implicated in Autosomal-Dominant Congenital Lower Urinary-Tract Obstruction

  • Am J Hum Genet. 2019 May 2;104(5):994-1006. doi: 10.1016/j.ajhg.2019.03.023.
Caroline M Kolvenbach 1,  Gabriel C Dworschak 2,  Sandra Frese 3,  Anna S Japp 4,  Peggy Schuster 5,  Nina Wenzlitschke 5,  Öznur Yilmaz 6,  Filipa M Lopes 7,  Alexey Pryalukhin 8,  Luca Schierbaum 3,  Loes F M van der Zanden 9,  Franziska Kause 10,  Ronen Schneider 11,  Katarzyna Taranta-Janusz 12,  Maria Szczepańska 13,  Krzysztof Pawlaczyk 14,  William G Newman 15,  Glenda M Beaman 15,  Helen M Stuart 15,  Raimondo M Cervellione 16,  Wouter F J Feitz 17,  Iris A L M van Rooij 18,  Michiel F Schreuder 19,  Martijn Steffens 20,  Stefanie Weber 21,  Waltraut M Merz 22,  Markus Feldkötter 23,  Bernd Hoppe 23,  Holger Thiele 24,  Janine Altmüller 25,  Christoph Berg 22,  Glen Kristiansen 15,  Michael Ludwig 26,  Heiko Reutter 27,  Adrian S Woolf 7,  Friedhelm Hildebrandt 11,  Phillip Grote 5,  Marcin Zaniew 28,  Benjamin Odermatt 29,  Alina C Hilger 30
Affiliations

Affiliations

  • 1 Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Institute of Anatomy, University of Bonn, 53115 Bonn, Germany; Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
  • 2 Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Institute of Anatomy, University of Bonn, 53115 Bonn, Germany; Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 3 Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
  • 4 Institute of Neuropathology, University of Bonn Medical Center, 53127 Bonn, Germany.
  • 5 Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe University, 60439 Frankfurt am Main, Germany.
  • 6 Institute of Anatomy, University of Bonn, 53115 Bonn, Germany.
  • 7 Division of Cell Matrix and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centere, Manchester M13 9PT, United Kingdom.
  • 8 Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany.
  • 9 Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 10 Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
  • 11 Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, United States.
  • 12 Department of Pediatrics and Nephrology, Medical University of Białystok, 15-089 Białystok, Poland.
  • 13 Department and Clinics of Pediatrics, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia in Katowice, 40-055 Zabrze, Poland.
  • 14 Department of Nephrology, Transplantology, and Internal Medicine, Poznan University of Medical Sciences, 61-701 Poznan, Poland.
  • 15 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, United Kingdom.
  • 16 Paediatric Urology, Royal Manchester Children's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom.
  • 17 Department of Urology, Pediatric Urology, Radboudumc Amalia Children's Hospital, 6525 GA Nijmegen, the Netherlands.
  • 18 Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Surgery-Pediatric Surgery, Radboudumc Amalia Children's Hospital, 6525 GA Nijmegen, the Netherlands.
  • 19 Department of Pediatric Nephrology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Amalia Children's Hospital, 6525 GA Nijmegen, the Netherlands.
  • 20 Department of Urology, Isala, 8025 AB Zwolle, the Netherlands.
  • 21 Department of Pediatrics, University Hospital Marburg, 35037 Marburg, Germany.
  • 22 Department of Obstetrics and Prenatal Medicine, University of Bonn, 53127 Bonn, Germany.
  • 23 Division of Pediatric Nephrology, Department of Pediatrics, University Hospital Bonn, 53129 Bonn, Germany.
  • 24 Cologne Center for Genomics, University of Cologne, 50391 Cologne, Germany.
  • 25 Cologne Center for Genomics, University of Cologne, 50391 Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, 50391 Cologne, Germany.
  • 26 Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53127 Bonn, Germany.
  • 27 Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, 53127 Bonn, Germany.
  • 28 Department of Pediatrics, University of Zielona Góra, 56-417 Zielona Góra, Poland.
  • 29 Institute of Anatomy, University of Bonn, 53115 Bonn, Germany; Institute of Neuro-Anatomy, University of Bonn, 53115 Bonn, Germany. Electronic address: [email protected].
  • 30 Department of Pediatrics, Children's Hospital, University Hospital Bonn, 53113 Bonn, Germany; Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany. Electronic address: [email protected].
PMID: 31051115 DOI: 10.1016/j.ajhg.2019.03.023
Abstract

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.

Keywords

BNC2; LUTO; basonuclin 2; cloacae; distal pronephric outlet obstruction; functional genetics; lower urinary tract obstruction; posterior urethral valve; pronephric development; zebrafish.

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