Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

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

doi:10.1086/512735

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

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 WoolfYi Rao, James R Lupski, Michael R Eccles, Bradley J Quade, James F Gusella, Cynthia C Morton, Richard L Maas

Division of Evolution, Infection and Genomics

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	616-32
Number of pages	17
Journal	American Journal of Human Genetics
Volume	80
Issue number	4
DOIs	https://doi.org/10.1086/512735
Publication status	Published - Apr 2007

Keywords

Amino Acid Sequence
Animals
Blotting, Southern
Blotting, Western
Cell Line
Chromosomes, Human, Pair 3
Chromosomes, Human, Y
DNA Mutational Analysis
DNA Primers
Genetic Predisposition to Disease
Humans
In Situ Hybridization, Fluorescence
Male
Mice
Molecular Sequence Data
Mutation, Missense
Nerve Tissue Proteins
Pedigree
Receptors, Immunologic
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Translocation, Genetic
Urinary Tract
Vesico-Ureteral Reflux
Comparative Study
Journal Article

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10.1086/512735

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Lu, W., van Eerde, A. M., Fan, X., Quintero-Rivera, F., Kulkarni, S., Ferguson, H., Kim, H.-G., Fan, Y., Xi, Q., Li, Q.-G., Sanlaville, D., Andrews, W., Sundaresan, V., Bi, W., Yan, J., Giltay, J. C., Wijmenga, C., de Jong, T. P. V. M., Feather, S. A., ... Maas, R. L. (2007). Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. American Journal of Human Genetics, 80(4), 616-32. https://doi.org/10.1086/512735

@article{75307060755348a8b8f04ffa4ade446d,

title = "Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux",

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.",

keywords = "Amino Acid Sequence, Animals, Blotting, Southern, Blotting, Western, Cell Line, Chromosomes, Human, Pair 3, Chromosomes, Human, Y, DNA Mutational Analysis, DNA Primers, Genetic Predisposition to Disease, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Molecular Sequence Data, Mutation, Missense, Nerve Tissue Proteins, Pedigree, Receptors, Immunologic, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Translocation, Genetic, Urinary Tract, Vesico-Ureteral Reflux, Comparative Study, Journal Article",

author = "Weining Lu and {van Eerde}, {Albertien M} and Xueping Fan and Fabiola Quintero-Rivera and Shashikant Kulkarni and Heather Ferguson and Hyung-Goo Kim and Yanli Fan and Qiongchao Xi and Qing-Gang Li and Damien Sanlaville and William Andrews and Vasi Sundaresan and Weimin Bi and Jiong Yan and Giltay, {Jacques C} and Cisca Wijmenga and {de Jong}, {Tom P V M} and Feather, {Sally A} and Woolf, {Adrian S} and Yi Rao and Lupski, {James R} and Eccles, {Michael R} and Quade, {Bradley J} and Gusella, {James F} and Morton, {Cynthia C} and Maas, {Richard L}",

year = "2007",

month = apr,

doi = "10.1086/512735",

language = "English",

volume = "80",

pages = "616--32",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Lu, W, van Eerde, AM, Fan, X, Quintero-Rivera, F, Kulkarni, S, Ferguson, H, Kim, H-G, Fan, Y, Xi, Q, Li, Q-G, Sanlaville, D, Andrews, W, Sundaresan, V, Bi, W, Yan, J, Giltay, JC, Wijmenga, C, de Jong, TPVM, Feather, SA, Woolf, AS, Rao, Y, Lupski, JR, Eccles, MR, Quade, BJ, Gusella, JF, Morton, CC & Maas, RL 2007, 'Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux', American Journal of Human Genetics, vol. 80, no. 4, pp. 616-32. https://doi.org/10.1086/512735

TY - JOUR

T1 - Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

AU - Lu, Weining

AU - van Eerde, Albertien M

AU - Fan, Xueping

AU - Quintero-Rivera, Fabiola

AU - Kulkarni, Shashikant

AU - Ferguson, Heather

AU - Kim, Hyung-Goo

AU - Fan, Yanli

AU - Xi, Qiongchao

AU - Li, Qing-Gang

AU - Sanlaville, Damien

AU - Andrews, William

AU - Sundaresan, Vasi

AU - Bi, Weimin

AU - Yan, Jiong

AU - Giltay, Jacques C

AU - Wijmenga, Cisca

AU - de Jong, Tom P V M

AU - Feather, Sally A

AU - Woolf, Adrian S

AU - Rao, Yi

AU - Lupski, James R

AU - Eccles, Michael R

AU - Quade, Bradley J

AU - Gusella, James F

AU - Morton, Cynthia C

AU - Maas, Richard L

PY - 2007/4

Y1 - 2007/4

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Blotting, Southern

KW - Blotting, Western

KW - Cell Line

KW - Chromosomes, Human, Pair 3

KW - Chromosomes, Human, Y

KW - DNA Mutational Analysis

KW - DNA Primers

KW - Genetic Predisposition to Disease

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Male

KW - Mice

KW - Molecular Sequence Data

KW - Mutation, Missense

KW - Nerve Tissue Proteins

KW - Pedigree

KW - Receptors, Immunologic

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Signal Transduction

KW - Translocation, Genetic

KW - Urinary Tract

KW - Vesico-Ureteral Reflux

KW - Comparative Study

KW - Journal Article

U2 - 10.1086/512735

DO - 10.1086/512735

M3 - Article

C2 - 17357069

SN - 0002-9297

VL - 80

SP - 616

EP - 632

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux

Abstract

Keywords

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