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

Caroline M Kolvenbach; Gabriel C Dworschak; Sandra Frese; Anna S Japp; Peggy Schuster; Nina Wenzlitschke; Öznur Yilmaz; Filipa M Lopes; Alexey Pryalukhin; Luca Schierbaum; Loes F M van der Zanden; Franziska Kause; Ronen Schneider; Katarzyna Taranta-Janusz; Maria Szczepańska; Krzysztof Pawlaczyk; William G Newman; Glenda M Beaman; Helen M Stuart; Raimondo M Cervellione; Wouter F J Feitz; Iris A L M van Rooij; Michiel F Schreuder; Martijn Steffens; Stefanie Weber; Waltraut M Merz; Markus Feldkötter; Bernd Hoppe; Holger Thiele; Janine Altmüller; Christoph Berg; Glen Kristiansen; Michael Ludwig; Heiko Reutter; Adrian S Woolf; Friedhelm Hildebrandt; Phillip Grote; Marcin Zaniew; Benjamin Odermatt; Alina C Hilger

doi:10.1016/j.ajhg.2019.03.023

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.

Authors

Caroline M Kolvenbach¹, Gabriel C Dworschak², Sandra Frese³, Anna S Japp⁴, Peggy Schuster⁵, Nina Wenzlitschke⁵, Öznur Yilmaz⁶, Filipa M Lopes⁷, Alexey Pryalukhin⁸, Luca Schierbaum³, Loes F M van der Zanden⁹, Franziska Kause¹⁰, Ronen Schneider¹¹, Katarzyna Taranta-Janusz¹², Maria Szczepańska¹³, Krzysztof Pawlaczyk¹⁴, William G Newman¹⁵, Glenda M Beaman¹⁵, Helen M Stuart¹⁵, Raimondo M Cervellione¹⁶, Wouter F J Feitz¹⁷, Iris A L M van Rooij¹⁸, Michiel F Schreuder¹⁹, Martijn Steffens²⁰, Stefanie Weber²¹, Waltraut M Merz²², Markus Feldkötter²³, Bernd Hoppe²³, Holger Thiele²⁴, Janine Altmüller²⁵, Christoph Berg²², Glen Kristiansen¹⁵, Michael Ludwig²⁶, Heiko Reutter²⁷, Adrian S Woolf⁷, Friedhelm Hildebrandt¹¹, Phillip Grote⁵, Marcin Zaniew²⁸, Benjamin Odermatt²⁹, Alina C Hilger³⁰

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Child
Chromosome Aberrations*
DNA-Binding Proteins / genetics*
Female
Fetal Diseases / genetics*
Fetal Diseases / pathology
Genes, Dominant
Gestational Age
Humans
Male
Mice
Middle Aged
Mutation*
Pedigree
Pregnancy
Urinary Bladder Neck Obstruction / congenital*
Urinary Bladder Neck Obstruction / genetics*
Urinary Bladder Neck Obstruction / pathology
Zebrafish

Substances

BNC2 protein, human
DNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding