ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

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

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Abstract: FR-OR037

Analysis of Humans and Mice with DSTYK Mutations Reveals Complex Association with Urinary Tract Malformations and Neurological Phenotypes

Session Information

Category: Genetic Diseases of the Kidney

  • 803 Genetic Epidemiology and Other Genetic Studies of Common Kidney Diseases

Authors

  • Martino, Jeremiah, Columbia University Medical Center, New York, New York, United States
  • Xuan, Shouhong, Columbia University Medical Center, New York, New York, United States
  • Perez, Alejandra, Columbia University College of Physicians & Surgeons, New York, New York, United States
  • Vukojevic, Katarina, University of Split School of Medicine, Split, Croatia
  • Liu, Qingxue, Columbia University Medical Center, New York, New York, United States
  • Westland, Rik, VU University Medical Center, Amsterdam, Netherlands
  • Mitrotti, Adele, Columbia University Medical Center, New York, New York, United States
  • Mendelsohn, Cathy, Columbia University Medical Center, New York, New York, United States
  • Goldstein, David B., Columbia University, New York, New York, United States
  • Gharavi, Ali G., Columbia University, New York, New York, United States
  • Sanna-Cherchi, Simone, Columbia University, New York, New York, United States
Background

Our previous work has shown that dominant splice-site or premature termination mutations in DSTYK produce urinary tract malformations associated with epilepsy/ataxia in humans.

Methods

We queried exome sequencing data from large datasets of epilepsy patients and controls. We analyzed Dstyk null mice and human DSTYK null 293T cells generated using CRISPR technology.

Results

We queried exome sequencing data for 11,081 epilepsy patients, and 36,952 in house controls. The disease-implicated splice variant c.654+1G>A is present in ~1 in 3,300 European individuals from ExAC, and in 12/36,952 house controls and 3/11,081 epilepsy patients, suggesting it may be an incompletely penetrant allele. Healthy controls were completely depleted of any DSTYK loss-of-function (LOF) mutations. We also identified a new splice mutation, absent in ExAC and all our controls, in monozygotic twins with bilateral congenital hydronephrosis, and two premature termination mutations in two epilepsy patients for whom renal history is not yet available. Inactivation of Dstyk in the mouse showed perinatal lethality at P0/P1 and CAKUT. We observed unilateral renal agenesis and hypoplasia, shortened ureters and pelvic kidneys, and bladder diverticuli. Age-dependent obstructive uropathy was observed in ~70% of Dstyk-/- embryos. Hydronephrosis, papillary septation and maldevelopment increased in severity with age. To gain more insight into molecular pathogenesis, we generated two compound heterozygous DSTYK-null clones in 293T cells. Analysis of RNA-seq data of WT and DSTYK null cells show alterations in cell adhesion and neurogenesis pathways, including altered signaling by BMP, FGF, NOTCH, and WNT pathways. Genes associated to monogenic forms of epilepsy (GABRB3, PCDH19, and PRRT2) and CAKUT (GDNF, ITGA8, GPC3) were also downregulated. Finally, DOK6, an adaptor protein that interacts with RET was also downregulated in the DSTYK null cells.

Conclusion

In summary, we identified novel LOF mutations in patients with epilepsy confirming a new potential clinical association, provide evidence for genetic causality for CAKUT based on gene inactivation in the mouse, and identified cellular pathways perturbed by DSTYK inactivation.

Funding

  • NIDDK Support