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. 

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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

Issue

Vol. 4 No. 2 (2016)

Section

Articles