title: Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract.
abstract: 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.forename: Xueping
authors.initials: X
authors.lastname: Fan
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.forename: Stefanie
authors.initials: S
authors.lastname: Chan
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Dworschak
authors.forename: Julian
authors.initials: J
authors.lastname: Schulz
authors.forename: Albertien M
authors.initials: AM
authors.lastname: van Eerde
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.forename: Heon Yung
authors.initials: HY
authors.lastname: Gee
authors.forename: Tracie
authors.initials: T
authors.lastname: Pennimpede
authors.forename: Bernhard G
authors.initials: BG
authors.lastname: Herrmann
authors.forename: Glenn
authors.initials: G
authors.lastname: van de Hoek
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Renkema
authors.forename: Christoph
authors.initials: C
authors.lastname: Schell
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Heiko M
authors.initials: HM
authors.lastname: Reutter
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.forename: Natasa
authors.initials: N
authors.lastname: Stajic
authors.forename: Radovan
authors.initials: R
authors.lastname: Bogdanovic
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.forename: Weining
authors.initials: W
authors.lastname: Lu
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D000818:Animals; D059472:Exome; D020690:GTPase-Activating Proteins / Q000096:biosynthesis / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D014564:Urogenital Abnormalities / Q000196:embryology / Q000235:genetics; D014718:Vesico-Ureteral Reflux / Q000196:embryology / Q000235:genetics; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
chemical_list: D020690:GTPase-Activating Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000098552:Slit Homolog 2 Protein; C498890:ROBO2 protein, human; D000097905:Roundabout Proteins; C498888:Robo2 protein, mouse; C516057:Robo2 protein, rat; C582067:SRGAP1 protein, human; C530213:srGAP1 protein, rat