Abstract: SA-PO586
Identifying Modifier Genes of X-Linked Alport Syndrome Using a Novel Multi-Parent Mouse Model
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- Korstanje, Ron, The Jackson Laboratory, Bar Harbor, Maine, United States
- Gatti, Daniel M, The Jackson Laboratory, Bar Harbor, Maine, United States
- Takemon, Yuka, The Jackson Laboratory, Bar Harbor, Maine, United States
Background
A major goal for precision medicine in genetic diseases is the identification of modifier genes as potential therapeutic targets. Using X-linked Alport Syndrome (XAS) as a model for heritable kidney diseases, we have developed a novel approach to identify modifier genes that modulate disease severity outcomes. To identify modifiers for XAS, we introduced a Col4a5 mutation into the genetically heterogeneous Diversity Outbred (DO) mice and conducted high-resolution mapping for several renal phenotypes.
Methods
The DO mice are an ideal population for high-precision genetic mapping, containing 45 million SNPs originating from 8 founder strains. The diversity captured in the DO emulates the variation in the human genome. To introduce XAS into the DO population, we crossed female C57BL/6J-Col4a5+/- mice with 100 unique male DO mice. From each mating we selected one Col4a5-/Y male and one Col4a5+/- female F1 offspring to create a cohort of 200 mice. We measured albuminuria (ACR) at 6, 10, and 15 weeks, and glomerular function (GFR) at 14 weeks of age. We genotyped each animal, reconstructed haplotypes, and mapped loci associated with variation in ACR and GFR.
Results
There was large variation in GFR and ACR in our cohort. Similar to human XAS patients, males had increased severity with elevated ACR and reduced GFR relative to females. High-resolution linkage and association mapping revealed several loci as narrow as 1Mbp harboring genes responsible for driving variation in ACR and GFR. The most significant GFR locus contains only 5 annotated genes, including a transcription factor regulating microtubule network related protein expression. Similarly, a locus for ACR contains a gene associated with actin filament formation. Both candidates suggest an affect on the structure and therefore the function of podocyte foot processes, critical for kidney health.
Conclusion
Our study successfully identified several novel candidate genes implicated in modifying XAS disease severity outcomes. These candidates are prime therapeutic targets for XAS. This work demonstrates the power of high-resolution genetic mapping in the DO mice, an approach that can be applied to other forms for heritable renal diseases such as polycystic kidney disease.
Funding
- Other NIH Support