A SAMD9L missense mutation drives autosomal dominant cystic kidney disease and c-Myc activation in mice

Certificate Output Instructions

For best output, select "Paper Size" as "A4" and "Margin" as "0" or "None".

To save or print to PDF, please select Print Destination > Save as PDF, enable Background Graphics under "More Settings", then click "Save".

Presented the abstract " "
(Abstract co-author(s): )

Back

E-Poster Presentation

During the congress, E-Posters will be accessible to all participants on the congress website 24/7, as well as in the E-poster stations in the congress center.

Preparing your E-Poster

Please review the E-Poster format requirements carefully when preparing your E-Poster. Should your E-Poster not meet the mentioned requirements, it may not be displayed as described above.

E-Poster Submission Deadline

Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.

E-Poster Format Requirements

PDF file
Layout: Portrait (vertical orientation)
One page only (Dim A4: 210 x 297mm or PPT)
E-Poster can be prepared in PowerPoint (one (1) PowerPoint slide) but must be saved and submitted as PDF file.
File Size: Maximum file size is 2 Megabytes (2 MB)
No hyperlinks, animated images, animations, and slide transitions
Language: English
Include your abstract number
E-posters can include QR codes, tables and photos

E-Poster

Abstract Title *

A SAMD9L missense mutation drives autosomal dominant cystic kidney disease and c-Myc activation in mice

Please follow the instructions below to input your abstract title.

Abstract titles should be brief and reflect the content of the abstract.

The title will not be accepted if it exceeds 25 words.
Type in CAPITAL LETTERS.
Lowercase may be used for abbreviations only, for example, mRNA.

Co-author 1

Homza Hireed homza.hireed@northwestern.edu Northwestern university Feinberg Cardiovascular and Renal Research Institute and Division of Nephrology Chicago United States -

Co-author 2

Dorian Kaminsky dorian.kaminski@yale.edu Yale University Department of Medicine New Haven United States -

Co-author 3

Joshua Waitzman jswaitzm@bidmc.harvard.edu Beth Israel Deaconess Division of Nephrology Boston United States -

Co-author 4

Joseph Ly jo.ly@me.com The Scarborough Hospital Internal Medicine Tronto Canada -

Co-author 5

Susan Quaggin quaggin@northwestern.edu Northwestern university Feinberg Cardiovascular and Renal Research Institute and Division of Nephrology Chicago United States -

Co-author 6

Hiroshi Maekawa black.doct@gmail..com Northwestern University einberg Cardiovascular and Renal Research Institute and Division of Nephrology Chicao United States *

Co-author 7

Co-author 8

Co-author 9

Co-author 10

Co-author 11

Co-author 12

Co-author 13

Co-author 14

Co-author 15

Introduction

Hereditary cystic kidney diseases are significant causes of renal impairment. We identified a novel missense mutation (S617T) in Samd9l gene, resulting in a cystic kidney phenotype in mice.

Methods

We used an autosomal-dominant phenotypic ENU mutagenesis screen in C3H mice to identify genes associated with kidney disease. F1 mice (C3HxC57Bl6J) were screened for renal phenotypes and heritability was confirmed by further backcrossing. SNP analysis was used to establish linkage between the genomic region and kidney phenotypes. Whole exome sequencing of genes within the critical linkage region was performed to identify genetic variants. Kidneys from variant mice at P0 and 40 weeks were analyzed. Transcriptomic profiling of the kidney was performed using bulk and single-cell RNA sequencing. To confirm causality through genetic non-complementation, SAMD9L S617T mice were bred with mice carrying another missense mutation (D764N) in the Samd9l gene.

Results

Using an ENU mutagenesis phenotypic screen, we identified a missense mutation in the Samd9L gene (S617T). Mice that are homozygous for S617T allele exhibited perinatal lethality with pulmonary, hepatic and cardiac hemorrhage, and renal cyst formation. While heterozygous mice developed normally, they had reduced levels of SAMD9L expression and developed glomerular and tubular cysts. Bulk and single-cell RNA seq of kidneys from P0 homozygous variants demonstrated upregulation of Myc pathway genes in nephron epithelial cells. At 40 weeks, heterozygous mice exhibited elevated c-Myc mRNA and protein levels in the kidney. Compound heterozygotes carrying two different mutations (SAMD9LS617T and SAMD9LD764N) 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.

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 represents a therapeutic target.

Kewords