ETV4 Mutation in a Patient with Congenital Anomalies of the Kidney and Urinary Tract

Authors

  • Jing Chen Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA and Department of Nephrology, Children’s Hospital of Fudan University, Shanghai, China
  • Amelie T. van der Ven Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Joseph A. Newman The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
  • Asaf Vivante Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA and Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel
  • Nina Mann Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Hazel Aitkenhead The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
  • Shirlee Shril Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Hadas Ityel Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Julian Schulz Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Johanna Magdalena Schmidt Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
  • Eugen Widmeier Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA and Department of Medicine, Renal Division, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Opher Gileadi The Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom
  • Frank Costantini Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA
  • Shifaan Thowfeequ Department of Genetics and Development, Columbia University Medical Center, New York, New York, USA
  • Roland H. Wenger Institute of Physiology and Zürich Center for Integrative Human Physiology (ZIHP), University of Zürich, Zürich, Switzerland
  • Stuart B. Bauer Department of Urology, Boston Children’s Hospital, Harvard Medical School, Massachusetts, USA
  • Richard S. Lee Department of Urology, Boston Children’s Hospital, Harvard Medical School, Massachusetts, USA
  • Weining Lu Renal Section, Department of Medicine, Boston University Medical Center, Boston, MA, USA
  • Maike Getwan Department of Medicine, Renal Division, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Michael M. Kaminski Department of Medicine, Renal Division, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Soeren S. Lienkamp Department of Medicine, Renal Division, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany and Center for Biological Signaling Studies (BIOSS), Freiburg, Germany
  • Richard P. Lifton Department of Human Genetics, Yale University School of Medicine, New Haven, CT, USA and Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
  • Velibor Tasic Medical Faculty Skopje, University Children’s Hospital, Skopje, Macedonia
  • Elijah O. Kehinde Division of Urology, Department of Surgery, Nazarbayev University, Astana, Kazakhstan
  • Friedhelm Hildebrandt Department of Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

DOI:

https://doi.org/10.12974/2311-8687.2016.04.02.1

Keywords:

CAKUT, cell migration, DNA binding, ETS domain.

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common reason for chronic kidney disease in children. Although more than 30 monogenic causes have been implicated in isolated forms of human CAKUT so far, the vast majority remains elusive. To identify novel monogenic causes of CAKUT we applied homozygosity mapping, together with whole exome sequencing, in a patient from consanguineous descent with isolated CAKUT. We identified a homozygous missense mutation (p.Arg415His) of the Ets Translocation Variant Gene 4 (ETV4). The transcription factor ETV4 is a downstream target of the GDNF/RET signaling pathway that plays a crucial role in kidney development. We show by means of electrophoretic mobility shift assay that the Arg415His mutant causes loss of the DNA binding affinity of ETV4 and fails to activate transcription in a cell-based luciferase reporter assay. We furthermore investigated the impact of the mutant protein on cell migration rate. Unlike wildtype ETV4, the Arg415His mutant failed to rescue cell migration defects observed in two ETV4 knock-down cell-lines. We therefore identified and functionally characterized a recessive mutation in ETV4 in a human patient with CAKUT. We hypothesize that the pathomechanism of this mutation could be via loss of the transcriptional function of ETV4, and a resulting abrogation of GDNF/RET/ETV4 signaling pathway. 

References

Ichikawa I, Kuwayama F, Pope JCt, Stephens FD and Miyazaki Y. Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney International 2002; 61(3): 889-98. https://doi.org/10.1046/j.1523-1755.2002.00188.x DOI: https://doi.org/10.1046/j.1523-1755.2002.00188.x

Pohl M, Bhatnagar V, Mendoza SA and Nigam SK. Toward an etiological classification of developmental disorders of the kidney and upper urinary tract. Kidney International 2002; 61(1): 10-9. https://doi.org/10.1046/j.1523-1755.2002.00086.x DOI: https://doi.org/10.1046/j.1523-1755.2002.00086.x

Smith JM, Stablein DM, Munoz R, Hebert D and McDonald RA. Contributions of the Transplant Registry: The 2006 Annual Report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS). Pediatric transplantation 2007; 11(4): 366-73. https://doi.org/10.1111/j.1399-3046.2007.00704.x DOI: https://doi.org/10.1111/j.1399-3046.2007.00704.x

Ingelfinger JR, Kalantar-Zadeh K and Schaefer F. World Kidney Day Steering C. World Kidney Day 2016: Averting the legacy of kidney disease-focus on childhood. Pediatric nephrology 2016; 31(3): 343-8. https://doi.org/10.1007/s00467-015-3255-7 DOI: https://doi.org/10.1007/s00467-015-3255-7

Vivante A, Kohl S, Hwang DY, Dworschak GC and Hildebrandt F. Single-gene causes of congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Pediatric nephrology 2014; 29(4): 695-704. https://doi.org/10.1007/s00467-013-2684-4 DOI: https://doi.org/10.1007/s00467-013-2684-4

Vivante A and Hildebrandt F. Exploring the genetic basis of early-onset chronic kidney disease. Nature reviews Nephrology 2016; 12(3): 133-46. https://doi.org/10.1038/nrneph.2015.205 DOI: https://doi.org/10.1038/nrneph.2015.205

Humbert C, Silbermann F, Morar B, Parisot M, Zarhrate M, Masson C, et al. Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. American journal of human genetics 2014; 94(2): 288-94. https://doi.org/10.1016/j.ajhg.2013.12.017 DOI: https://doi.org/10.1016/j.ajhg.2013.12.017

Barak H, Huh SH, Chen S, Jeanpierre C, Martinovic J, Parisot M, et al. FGF9 and FGF20 maintain the stemness of nephron progenitors in mice and man. Developmental cell 2012; 22(6): 1191-207. https://doi.org/10.1016/j.devcel.2012.04.018 DOI: https://doi.org/10.1016/j.devcel.2012.04.018

Vivante A, Kleppa MJ, Schulz J, Kohl S, Sharma A, Chen J, et al. Mutations in TBX18 Cause Dominant Urinary Tract Malformations via Transcriptional Dysregulation of Ureter Development. American journal of human genetics 2015; 97(2): 291-301. https://doi.org/10.1016/j.ajhg.2015.07.001 DOI: https://doi.org/10.1016/j.ajhg.2015.07.001

Hwang DY, Kohl S, Fan X, Vivante A, Chan S, Dworschak GC, et al. Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Human genetics 2015; 134(8): 905-16. https://doi.org/10.1007/s00439-015-1570-5 DOI: https://doi.org/10.1007/s00439-015-1570-5

Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, et al. Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. Journal of the American Society of Nephrology: JASN 2014; 25(9): 1917-22. https://doi.org/10.1681/ASN.2013101103 DOI: https://doi.org/10.1681/ASN.2013101103

Saisawat P, Kohl S, Hilger AC, Hwang DY, Yung Gee H, Dworschak GC, et al. Whole-exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney international 2014; 85(6): 1310-7. https://doi.org/10.1038/ki.2013.417 DOI: https://doi.org/10.1038/ki.2013.417

Cooper CD, Newman JA and Gileadi O. Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition. Biochemical Society transactions 2014; 42(1): 130-8. https://doi.org/10.1042/BST20130227 DOI: https://doi.org/10.1042/BST20130227

Lu BC, Cebrian C, Chi X, Kuure S, Kuo R, Bates CM, et al. ETV4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nature genetics 2009; 41(12): 1295-302. https://doi.org/10.1038/ng.476 DOI: https://doi.org/10.1038/ng.476

Riccio P, Cebrian C, Zong H, Hippenmeyer S and Costantini F. Ret and ETV4 Promote Directed Movements of Progenitor Cells during Renal Branching Morphogenesis. PLoS biology 2016; 14(2): e1002382. https://doi.org/10.1371/journal.pbio.1002382 DOI: https://doi.org/10.1371/journal.pbio.1002382

Marra AN and Wingert RA. Epithelial cell fate in the nephron tubule is mediated by the ETS transcription factors etv5a and ETV4 during zebrafish kidney development. Developmental biology 2016; 411(2): 231-45. https://doi.org/10.1016/j.ydbio.2016.01.035 DOI: https://doi.org/10.1016/j.ydbio.2016.01.035

Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst WL, et al. Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nature genetics 2016; 48(4): 457-65. https://doi.org/10.1038/ng.3512 DOI: https://doi.org/10.1038/ng.3512

Seelow D, Schuelke M, Hildebrandt F and Nurnberg P. HomozygosityMapper--an interactive approach to homozygosity mapping. Nucleic acids research 2009; 37(Web Server issue): W593-9. DOI: https://doi.org/10.1093/nar/gkp369

Upadhyay S, Liu C, Chatterjee A, Hoque MO, Kim MS, Engles J, et al. LKB1/STK11 suppresses cyclooxygenase-2 induction and cellular invasion through PEA3 in lung cancer. Cancer research 2006; 66(16): 7870-9. https://doi.org/10.1158/0008-5472.CAN-05-2902 DOI: https://doi.org/10.1158/0008-5472.CAN-05-2902

Huang WY, Xie W, Guo X, Li F, Jose PA and Chen SY. Smad2 and PEA3 cooperatively regulate transcription of response gene to complement 32 in TGF-beta-induced smooth muscle cell differentiation of neural crest cells. American journal of physiology Cell physiology 2011; 301(2): C499-506. https://doi.org/10.1152/ajpcell.00480.2010 DOI: https://doi.org/10.1152/ajpcell.00480.2010

Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, et al. Mutations in 12 known dominant diseasecausing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney international 2014; 85(6): 1429-33. https://doi.org/10.1038/ki.2013.508 DOI: https://doi.org/10.1038/ki.2013.508

Guo B, Panagiotaki N, Warwood S and Sharrocks AD. Dynamic modification of the ETS transcription factor PEA3 by sumoylation and p300-mediated acetylation. Nucleic acids research 2011; 39(15): 6403-13. https://doi.org/10.1093/nar/gkr267 DOI: https://doi.org/10.1093/nar/gkr267

Bojovic BB and Hassell JA. The PEA3 Ets transcription factor comprises multiple domains that regulate transactivation and DNA binding. The Journal of biological chemistry 2001; 276(6): 4509-21. https://doi.org/10.1074/jbc.M005509200 DOI: https://doi.org/10.1074/jbc.M005509200

Kuure S, Chi X, Lu B and Costantini F. The transcription factors ETV4 and Etv5 mediate formation of the ureteric bud tip domain during kidney development. Development 2010; 137(12): 1975-9. https://doi.org/10.1242/dev.051656 DOI: https://doi.org/10.1242/dev.051656

Cooper CD, Newman JA, Aitkenhead H, Allerston CK and Gileadi O. Structures of the Ets Protein DNA-binding Domains of Transcription Factors Etv1, ETV4, Etv5, and Fev: Determinants of Dna Binding and Redox Regulation by Disulfide Bond Formation. The Journal of biological chemistry 2015; 290(22): 13692-709. https://doi.org/10.1074/jbc.M115.646737 DOI: https://doi.org/10.1074/jbc.M115.646737

Wollenick K, Hu J, Kristiansen G, Schraml P, Rehrauer H, Berchner-Pfannschmidt U, et al. Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxiainducible factor signaling. Nucleic acids research 2012; 40(5): 1928-43. https://doi.org/10.1093/nar/gkr978 DOI: https://doi.org/10.1093/nar/gkr978

Livet J, Sigrist M, Stroebel S, De Paola V, Price SR, Henderson CE, et al. ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 2002; 35(5): 877-92. https://doi.org/10.1016/S0896-6273(02)00863-2 DOI: https://doi.org/10.1016/S0896-6273(02)00863-2

Zhang Z, Verheyden JM, Hassell JA and Sun X. FGFregulated Etv genes are essential for repressing Shh expression in mouse limb buds. Developmental cell 2009; 16(4): 607-13. https://doi.org/10.1016/j.devcel.2009.02.008 DOI: https://doi.org/10.1016/j.devcel.2009.02.008

Hollenhorst PC, McIntosh LP and Graves BJ. Genomic and biochemical insights into the specificity of ETS transcription factors. Annual review of biochemistry 2011; 80: 437-71. https://doi.org/10.1146/annurev.biochem.79.081507.103945 DOI: https://doi.org/10.1146/annurev.biochem.79.081507.103945

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Published

2016-09-04

How to Cite

Chen, J., van der Ven, A. T. ., Newman, J. A., Vivante, A., Mann, N., Aitkenhead, H., Shril, S., Ityel, H., Schulz, J., Schmidt, J. M., Widmeier, E., Gileadi, O., Costantini, F., Thowfeequ, S., Wenger, R. H., Bauer, S. B., Lee, R. S., Lu, W., Getwan, M., Kaminski, M. M., Lienkamp, S. S., Lifton, R. P., Tasic, V., Kehinde, E. O., & Hildebrandt, F. (2016). ETV4 Mutation in a Patient with Congenital Anomalies of the Kidney and Urinary Tract. International Journal of Pediatrics and Child Health, 4(2), 61–71. https://doi.org/10.12974/2311-8687.2016.04.02.1

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