Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract

TY - JOUR

T1 - Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract

AU - Hwang, Daw-Yang

AU - Kohl, Stefan

AU - Fan, Xueping

AU - Vivante, Asaf

AU - Chan, Stefanie

AU - Dworschak, Gabriel C

AU - Schulz, Julian

AU - van Eerde, Albertien M

AU - Hilger, Alina C

AU - Gee, Heon Yung

AU - Pennimpede, Tracie

AU - Herrmann, Bernhard G

AU - van de Hoek, Glenn

AU - Renkema, Kirsten Y

AU - Schell, Christoph

AU - Huber, Tobias B

AU - Reutter, Heiko M

AU - Soliman, Neveen A

AU - Stajic, Natasa

AU - Bogdanovic, Radovan

AU - Kehinde, Elijah O

AU - Lifton, Richard P

AU - Tasic, Velibor

AU - Lu, Weining

AU - Hildebrandt, Friedhelm

PY - 2015/8

Y1 - 2015/8

N2 - Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.

AB - Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-50% of chronic kidney disease that manifests in the first two decades of life. Thus far, 31 monogenic causes of isolated CAKUT have been described, explaining ~12% of cases. To identify additional CAKUT-causing genes, we performed whole-exome sequencing followed by a genetic burden analysis in 26 genetically unsolved families with CAKUT. We identified two heterozygous mutations in SRGAP1 in 2 unrelated families. SRGAP1 is a small GTPase-activating protein in the SLIT2-ROBO2 signaling pathway, which is essential for development of the metanephric kidney. We then examined the pathway-derived candidate gene SLIT2 for mutations in cohort of 749 individuals with CAKUT and we identified 3 unrelated individuals with heterozygous mutations. The clinical phenotypes of individuals with mutations in SLIT2 or SRGAP1 were cystic dysplastic kidneys, unilateral renal agenesis, and duplicated collecting system. We show that SRGAP1 is expressed in early mouse nephrogenic mesenchyme and that it is coexpressed with ROBO2 in SIX2-positive nephron progenitor cells of the cap mesenchyme in developing rat kidney. We demonstrate that the newly identified mutations in SRGAP1 lead to an augmented inhibition of RAC1 in cultured human embryonic kidney cells and that the SLIT2 mutations compromise the ability of the SLIT2 ligand to inhibit cell migration. Thus, we report on two novel candidate genes for causing monogenic isolated CAKUT in humans.

KW - Animals

KW - Exome

KW - GTPase-Activating Proteins

KW - HEK293 Cells

KW - Humans

KW - Intercellular Signaling Peptides and Proteins

KW - Mesoderm

KW - Mice

KW - Mutation

KW - Nerve Tissue Proteins

KW - Rats

KW - Receptors, Immunologic

KW - Risk Factors

KW - Signal Transduction

KW - Urogenital Abnormalities

KW - Vesico-Ureteral Reflux

KW - Clinical Trial

KW - Journal Article

KW - Multicenter Study

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s00439-015-1570-5

DO - 10.1007/s00439-015-1570-5

M3 - SCORING: Journal article

C2 - 26026792

VL - 134

SP - 905

EP - 916

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 8

ER -