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Abstract: FR-PO347

Novel Missense Mutation in SAMD9L Linked to Autosomal Dominant Cystic Kidney Disease in Mice Associated With Proteostastic Stress and Metabolic Reprogramming

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Kaminski, Dorian, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Zhou, Yalu, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Deb, Dilip K., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Waitzman, Joshua S., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Quaggin, Susan E., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Genetic cystic kidney syndromes, including polycystic kidney disease and nephronophthisis, are important causes of renal impairment. Here, we present a cystic kidney phenotype in mice carrying a novel missense mutation in SAMD9L, a gene that has previously been implicated in congenital autoinflammatory disorders and pediatric myelodysplastic syndrome.


An ENU mutagenesis library was screened for renal phenotypes and mutant mouse strains were established via backcrossing. The candidate gene was identified via mutation mapping, exome capture, high throughput sequencing on the SOLiD 4 platform (Applied BioSystems) and confirmed via whole-genome sequencing on the Illumina XTen machine. The phenotype was characterized via whole-body imaging, histology, immunoblotting, bulk RNAseq, and scRNA-seq on the 10x platform.


A mutant with cystic kidneys was identified. While heterozygous mice exhibited a renal-restricted phenotype inherited in an autosomal dominant fashion, homozygous mutants exhibited perinatal lethality due to vascular anomalies and hypoxia. The trait was inherited in Mendelian ratios. Mutation mapping and high throughput sequencing revealed a critical region on Chr6 containing an A->T transversion in the coding region of SAMD9L. Kidney histology renal cysts along the entire length of the nephron and collecting system, including glomerulocysts. Bulk and scRNAseq of mutant kidneys revealed differential expression of several hundred genes, but not genes previously implicated in inherited cystic kidney disease. In homozygous mutants, there was marked differential expression of genes involved in the unfolded protein response, c-Myc sigaling, and fatty acid oxidation. In heterozygous mutants, a similar but attenuated transcript signature was seen in differentiated nephron progenitors and mature epithelial clusters.


We identified a novel missense mutation in SAMD9L that resulted in a severe cystic kidney phenotype, with associated perturbations in proteostatic stress pathways and metabolism. Future experiments will include in vivo metabolic flux analysis and in vitro measurement of translation dynamics in a cell culture model.