ETV4 Mutation in a Patient with Congenital Anomalies of the Kidney and Urinary Tract
DOI:
https://doi.org/10.12974/2311-8687.2016.04.02.1Keywords:
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