Kidney Week

Abstract: FR-PO0064

A Samd9l Missense Variant Drives Autosomal Dominant Cystic Kidney Disease and c-Myc Activation in Mice

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

• Hireed, Homza, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Homza Hireed

• Maekawa, Hiroshi, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Hiroshi Maekawa, MD, PhD

• Kaminski, Dorian, Yale School of Medicine, New Haven, Connecticut, United States

Dorian Kaminski, MD

• Waitzman, Joshua S., Beth Israel Deaconess Hospital Department of Medicine, Boston, Massachusetts, United States

Joshua S. Waitzman, MD, PhD, FASN

• Ly, Joseph P., University of Toronto, Toronto, Ontario, Canada

Joseph P. Ly, MD

• Abdulkadir, Sarki A., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Sarki A. Abdulkadir, MD, PhD

• Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Susan E. Quaggin, MD, FASN

Background

Hereditary cystic kidney diseases are significant causes of renal impairment. We identified a novel Samd9l missense mutation, S617T, causing a cystic kidney phenotype in mice. Given c-MYC upregulation in mutant mice, we tested whether pharmacologic c-MYC inhibition could reduce renal c-MYC protein levels in vivo.

Methods

We used an autosomal-dominant ENU mutagenesis screen in C3H mice to identify kidney disease genes. F1 mice (C3HxC57Bl6J) were screened for renal phenotypes, and heritability was confirmed by backcrossing. SNP analysis established linkage between the genomic region and kidney phenotypes. Whole-exome sequencing within the critical linkage region identified genetic variants. Kidneys from variant mice at P0 and 40 weeks were analyzed. Renal transcriptomic profiling was performed using bulk and single-cell RNA sequencing. Genetic non-complementation was tested by breeding SAMD9L^S617T mice with mice carrying a second Samd9l missense mutation, D764N. To assess c-MYC pathway dependence, wild-type and compound heterozygous mice were treated with the c-MYC inhibitor 975i for 7 days, followed by histologic and protein analysis of harvested kidneys..

Results

ENU screening identified a missense mutation in Samd9l, S617T. Homozygous S617T mice exhibited perinatal lethality with pulmonary, hepatic, and cardiac hemorrhage and renal cyst formation. While heterozygous mice developed normally, they had reduced SAMD9L expression and developed glomerular and tubular cysts. Bulk and single-cell RNA-seq of P0 homozygous kidneys demonstrated upregulation of Myc pathway genes in nephron epithelial cells. At 40 weeks, heterozygous mice exhibited elevated renal c-Myc mRNA and protein. Compound heterozygotes carrying two mutations, SAMD9L^S617T and SAMD9L^D764N, exhibited increased early mortality and more severe renal cysts than single heterozygotes. C-Myc expression and Ki67-positive cells were more prominent in kidneys and cysts from compound heterozygotes, confirming genetic enhancement. Compound heterozygous mice treated with 975i showed robust reduction in renal c-MYC protein, consistent with pharmacologic suppression of c-MYC signaling.

Conclusion

We identified a novel SAMD9L missense mutation linked to cystic kidney disease and c-Myc dysregulation. Aberrant Myc signaling may drive cystic kidney disease and represent a therapeutic target.