@article{01GJQDNNQDMV8QSF4Y3RSB5V21,
  abstract     = {{Background: About 40 disease genes have been described to date for isolated congenital anomalies of the kidneys and urinary tract (CAKUT), the most common cause of childhood chronic kidney disease. However, these genes account for only 20% of cases. ARHGEF6, a guanine nucleotide exchange factor that is implicated in such biologic processes as cell migration and focal adhesion, acts downstream of integrin linked kinase (ILK) and parvin proteins. A genetic variant of ILK that causes murine renal agenesis abrogates the interaction of ILK with a murine focal adhesion protein encoded by Parva, leading to CAKUT in mice with this variant.

Methods: To identify novel genes that, when mutated, result in CAKUT, we performed exome sequencing in an international cohort of 1265 families with CAKUT. We also assessed the effects in vitro of wild-type and mutant ARHGEF6 proteins, as well as the effects of Arhgef6 deficiency in mouse and frog models.

Results: We detected six different hemizygous variants in the gene ARHGEF6 (which is located on the X chromosome in humans) in eight individuals from six families with CAKUT. In kidney cells, overexpression of wild-type ARHGEF6—but not proband-derived mutant ARHGEF6— increased active levels of CDC42/RAC1, induced lamellipodia formation, and stimulated PARVAdependent cell spreading. ARHGEF6 mutant proteins showed loss of interaction with PARVA. Three-dimensional MDCK cell cultures expressing ARHGEF6 mutant proteins exhibited reduced lumen formation and polarity defects. Arhgef6 deficiency in mouse and frog models recapitulated features of human CAKUT.

Conclusions: Deleterious variants in ARHGEF6 may cause dysregulation of integrin-parvinRAC1/CDC42 signaling, thereby leading to X-linked CAKUT.}},
  author       = {{Klämbt, V. and Buerger, F. and Wang, C. and Naert, Thomas and Richter, K. and Nauth, T. and Weiss, A. C. and Sieckmann, T. and Lai, E. and Connaughton, D. and Seltzsam, S. and Mann, N. and Majmundar, A. and Wu, C. H. and Onuchic-Whitford, A. and Shril, S. and Schneider, S. and Schierbaum, L. and Dai, R. and Bekheirnia, M. R. and Joosten, M. and Shlomovitz, O. and Vivante, A. and Banne, E. and Mane, S. and Lifton, R. P. and Kirschner, K. and Kispert, A. and Rosenberger, G. and Fischer, K. D. and Lienkamp, S. and Zegers, M. and Hildebrandt, F.}},
  issn         = {{1046-6673}},
  journal      = {{JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY}},
  keywords     = {{CAKUT,monogenic kidney disease,development,pediatric,urinary tract,REGULATES BRANCHING MORPHOGENESIS,NUCLEOTIDE EXCHANGE FACTORS,INTEGRIN-LINKED KINASE,MDCK CELL-CULTURE,ALPHA-PIX,EXTRACELLULAR-MATRIX,PROTEIN NEPHRONECTIN,INBRED MOUSE,MUTATIONS,SEQUENCE}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{273--290}},
  title        = {{Genetic variants in ARHGEF6 cause congenital anomalies of the kidneys and urinary tract in humans, mice, and frogs}},
  url          = {{http://doi.org/10.1681/asn.2022010050}},
  volume       = {{34}},
  year         = {{2023}},
}

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