Disruption of ROBO2 is Associated with Urinary Tract Anomalies and Confers Risk of Vesicoureteral Reflux

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2007 Mar 16

PMID 17357069

Citations 109

Authors

Weining Lu

Albertien M van Eerde

Xueping Fan

Fabiola Quintero-Rivera

Shashikant Kulkarni

Heather Ferguson

Hyung-Goo Kim

Yanli Fan

Qiongchao Xi

Qing-Gang Li

Damien Sanlaville

William Andrews

Vasi Sundaresan

Weimin Bi

Jiong Yan

Jacques C Giltay

Cisca Wijmenga

Tom P V M de Jong

Sally A Feather

Adrian S Woolf

Yi Rao

James R Lupski

Michael R Eccles

Bradley J Quade

James F Gusella

Cynthia C Morton

Richard L Maas

Affiliations

Soon will be listed here.

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR). VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults. We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects. This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro. In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families. Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes. Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR.

Citing Articles

Pathophysiology of Congenital Anomalies of the Kidney and Urinary Tract: A Comprehensive Review.

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A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT.

Mitrovic K, Zivotic I, Kolic I, Zakula J, Zivkovic M, Stankovic A BMC Genomics. 2024; 25(1):218.

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Islet architecture in adult mice is actively maintained by Robo2 expression in β cells.

Waters B, Birman Z, Wagner M, Lemanski J, Blum B Dev Biol. 2023; 505:122-129.

PMID: 37972678 PMC: 10841604. DOI: 10.1016/j.ydbio.2023.11.003.

The genetics and pathogenesis of CAKUT.

Kolvenbach C, Shril S, Hildebrandt F Nat Rev Nephrol. 2023; 19(11):709-720.

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