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

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• 作者：Daw-Yang Hwang ; Stefan Kohl ; Xueping Fan ; Asaf Vivante ; Stefanie Chan…
• 刊名：Human Genetics
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：134
• 期：8
• 页码：905-916
• 全文大小：3,502 KB
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• 作者单位：Daw-Yang Hwang (1) (12)
  Stefan Kohl (1)
  Xueping Fan (2)
  Asaf Vivante (1)
  Stefanie Chan (2)
  Gabriel C. Dworschak (1) (4)
  Julian Schulz (1)
  Albertien M. van Eerde (3)
  Alina C. Hilger (4)
  Heon Yung Gee (1)
  Tracie Pennimpede (5)
  Bernhard G. Herrmann (5)
  Glenn van de Hoek (3)
  Kirsten Y. Renkema (3)
  Christoph Schell (13) (19) (6)
  Tobias B. Huber (14) (6)
  Heiko M. Reutter (15) (4)
  Neveen A. Soliman (16) (7)
  Natasa Stajic (17) (8)
  Radovan Bogdanovic (17) (8)
  Elijah O. Kehinde (9)
  Richard P. Lifton (10) (18) (20)
  Velibor Tasic (11)
  Weining Lu (2)
  Friedhelm Hildebrandt (1) (20)
  
  1. Division of Nephrology, Department of Medicine, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
  12. Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
  2. Renal Section, Department of Medicine, Boston University Medical Center, 650 Albany Street, Boston, MA, 02118, USA
  4. Institute of Human Genetics, University of Bonn, Bonn, Germany
  3. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  5. Developmental Genetics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany
  13. Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University, Freiburg, Germany
  19. Faculty of Biology, Albert-Ludwigs-University, Freiburg, Germany
  6. Renal Division, University Hospital Freiburg, Freiburg, Germany
  14. BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany
  15. Department of Neonatology, Children’s Hospital, University of Bonn, Bonn, Germany
  16. Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt
  7. Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt
  17. Institute of Mother and Child Healthcare of Serbia, Belgrade, Serbia
  8. Medical Faculty, University of Belgrade, Belgrade, Serbia
  9. Department of Surgery, Kuwait University, Safat, Kuwait
  10. Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
  18. Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT, USA
  20. Howard Hughes Medical Institute, Chevy Chase, MD, USA
  11. Department of Pediatric Nephrology, University Children’s Hospital, Skopje, Macedonia
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Human Genetics
  Molecular Medicine
  Internal Medicine
  Metabolic Diseases
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1203

文摘

Congenital anomalies of the kidney and urinary tract (CAKUT) account for 40-0?% 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.