ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO784

Whole-Exome Sequencing Identifies Mutations in ARHGEF6 as a Potential Novel Monogenic Cause of Congenital Anomalies of the Kidney and Urinary Tract

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
  • Mao, Youying, Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Wu, Chen-Han Wilfred, Boston Children's Hospital, Boston, Massachusetts, United States
  • Bekheirnia, Mir Reza, Baylor College of Medicine, Houston, Texas, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first 3 decades of life. Although over 40 monogenic genes have been implicated in human CAKUT so far, many causes remain elusive.

Methods

In order to identify novel monogenic causes of CAKUT we performed whole exome sequencing (WES) in 514 families with CAKUT.

Results

By WES, we discovered a missense mutation (p.I444N) in the X-linked gene ARHGEF6 in 3 affected male subjects of family A5124 with CAKUT. Evaluation of our WES data of 514 unsolved CAKUT families revealed 3 further hemizygous ARHGEF6 mutations in 3 families (family GM1: p.R191*; B1185: p.L387Afs*58; GM2: c.2135+4A>G, splice). Affected individuals exhibited a spectrum of CAKUT phenotypes that correlated in severity with the underlying mutation: renal agenesis, bladder exstrophy, VUR, PUV with hydronephrosis, renal hypoplasia and hypospadias. The 2 patients with loss-of-function mutations also had extrarenal features (cardiomyopathy; extra vertebra). No pathogenic variants in ARHGEF6 were present in a control cohort of 100 NS and 258 NPHP cases. All variants, except p.I444N, were absent from gnomAD. ARHGEF6 encodes a guanine nucleotide exchange factor for the small GTPases CDC42 and RAC1, and has been implicated in various biological functions including cell migration. Both small GTPases play a role in kidney development, such as the requirement of Cdc42 for normal tubulogenesis in ureteric bud and metanephric mesenchyme development (J Cell Sci; 128:4293, 2015).
Overexpression in HEK293 cells of ARHGEF6 wildtype cDNA, but not of patient mutants, activated CDC42 and RAC1, while ARHGEF6 knockout cells reduced CDC42 activity.

Conclusion

We identified likely disease-causing mutations in ARHGEF6 in 4 unrelated families with CAKUT. Our findings suggest that dysregulation of CDC42 or RAC1 via ARHGEF6 dysfunction may cause CAKUT.

Funding

  • NIDDK Support