Open Access

Caroline Kolvenbach, Gabriel Clemens Dworschak, Sandra Frese, Anna Sophia 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 Stuart, Raimondo M. Cervellione, Wouter F. J. Feitz, Iris Antonia Leonarda Martina van Rooij, Michiel F. Schreuder, Martijn Steffens, Stefanie Weber, Waltraut Maria 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 Christine Hilger

• 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.