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

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.

SLC20A1 Is Involved in Urinary Tract and Urorectal Development

“…Human tissues, collected after maternal consent and ethical approval (REC 08/H0906/21 + 5), were provided by the MRC and Wellcome Trust Human Developmental Biology Resource 2 . Paraffin sections were processed for immunostaining after antigen retrieval, essentially as described ( Kolvenbach et al, 2019 ). Sections were probed with antibody to SLC20A1 (1:200; Proteintech 12423-1-AP).…”

“…Due to their ease of molecular manipulation and real-time observation, and the high fecundity of the species, we successfully used zebrafish larvae (zfl) to functionally characterize dominant variants reported in individuals with lower urinary tract obstruction (Kolvenbach et al, 2019). Here, we apply a similar zf model to investigate the role of slc20a1a in the zf urinary tract and urorectal development, and we combine this with human genomic, cell culture, and immunohistochemistry with regard to SLC20A1.…”

Congenital Disorders of the Human Urinary Tract: Recent Insights From Genetic and Molecular Studies

“…Two studies (97, 98) have reported on a variety of copy number variants in patients with posterior urethral valves but a convincing pattern or stronger evidence of pathogenicity yet to emerge for these. Of note, a preliminary study reported multiple members over three generations affected by anatomical uretral obstruction who carried a heterozygous non-sense mutation of BNC2 (99). This gene codes for basonuclin 2 a zinc finger protein that is expressed in the embryonic urethra (99).…”

“…Of note, a preliminary study reported multiple members over three generations affected by anatomical uretral obstruction who carried a heterozygous non-sense mutation of BNC2 (99). This gene codes for basonuclin 2 a zinc finger protein that is expressed in the embryonic urethra (99). Furthermore, experimental downregulation of the homologous gene in zebrafish caused malformation of the distal part of the embryonic urinary tract (99), and mutant Bnc2 mice have malformed urethras (100).…”

“…This gene codes for basonuclin 2 a zinc finger protein that is expressed in the embryonic urethra (99). Furthermore, experimental downregulation of the homologous gene in zebrafish caused malformation of the distal part of the embryonic urinary tract (99), and mutant Bnc2 mice have malformed urethras (100).…”