Abstract: FR-PO0077
Somatic Variants in a Pig Model of Early ADPKD
Session Information
- ADPKD and Cystic Kidney Disease - 2
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Yu, Alan S.L., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Wallace, Darren P., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Griffard-Smith, Rachel, The University of Kansas Medical Center, Kansas City, Kansas, United States
- Parnell, Stephen C., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Ward, Christopher J., The University of Kansas Medical Center, Kansas City, Kansas, United States
- Bishop, Brian, Exemplar Genetics, Coralville, Iowa, United States
- Rogers, Christopher S., Exemplar Genetics, Coralville, Iowa, United States
- Pei, Dong, The University of Kansas Medical Center, Kansas City, Kansas, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is caused by heterozygous germline loss-of-function mutations in the PKD1 and PKD2 genes. The pathogenesis of kidney cysts has been attributed to a "two-hit" mechanism in which a somatic mutation of either PKD gene in a tubule epithelial cell leads to a cellular recessive state and clonal proliferation. However, the only available evidence is from bulk sequencing of kidney cysts in older patients with end-stage kidney failure without control, non-cystic tissue for comparison. It is therefore unknown if ADPKD-causative somatic mutations occur in early disease, if cysts are truly clonal, if the observed mutations are absent from non-cystic kidney tissue, and therefore whether they are truly driver or merely passenger mutations. Rodent orthologous PKD models are recessive and therefore uninformative for human disease.
Methods
ADPKD pigs heterozygous for a loss-of-function Pkd1 allele were generated by gene targeting and somatic cell nuclear transfer. Kidneys from 3 pigs were harvested at 6–8 months of age. Epithelial cells were isolated from 6 individual cysts (15–25 mm diameter) and 2 control, non-cystic tissue samples for single cell genomic DNA sequencing of the Pkd1 and Pkd2 genes.
Results
Heterozygous Pkd1 pigs developed autosomal dominant polycystic kidney disease with a median of 7 cysts per kidney at time of euthanasia. A mean of 8,855 cells per sample (range 1,653–24,946) were sequenced, with a mean read depth per cell of 236 (range 87–608). By unsupervised clustering based on variant profiles, none of the cysts were found to be clonal. Eleven likely pathogenic short variants in Pkd1 or Pkd2 were observed, but these occurred with similar low frequency in cyst (5.5 ± 8.0%) and non-cystic (3.7 ± 4.2%) samples, and none drove clustering. A region of loss of heterozygosity indicative of partial deletion of the 5' end of the Pkd2 gene was observed in two animals, but was also present in both cyst and non-cystic samples.
Conclusion
No somatic driver mutations in Pkd1 or Pkd2, defined as likely pathogenic variants or copy number variation in Pkd1 or Pkd2 occurring in a subclone of cells in cyst samples and absent from non-cystic cells, were found. ADPKD in pigs is therefore unlikely to be due to a two-hit mechanism. Our study did uncover a surprisingly high rate of somatic mosaicism that may account for previous findings in end-stage human kidneys.
Funding
- Other U.S. Government Support