Uncovering modifier genes of X-linked Alport syndrome using a novel multiparent mouse model

Y Takemon, V Wright, B Davenport… - Journal of the …, 2021 - journals.lww.com
Y Takemon, V Wright, B Davenport, DM Gatti, SM Sheehan, K Letson, HS Savage, R Lennon
Journal of the American Society of Nephrology, 2021journals.lww.com
Background Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport
Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS
who have similar genetic mutations present with a wide variation in the extent of kidney
impairment and age of onset, suggesting the activities of modifier genes. Methods We
created a cohort of genetically diverse XLAS male and female mice using the Diversity
Outbred mouse resource and measured albuminuria, GFR, and gene expression. Using a …
Background
Mutations in COL4A5 are responsible for 80% of cases of X-linked Alport Syndrome (XLAS). Although genes that cause AS are well characterized, people with AS who have similar genetic mutations present with a wide variation in the extent of kidney impairment and age of onset, suggesting the activities of modifier genes.
Methods
We created a cohort of genetically diverse XLAS male and female mice using the Diversity Outbred mouse resource and measured albuminuria, GFR, and gene expression. Using a quantitative trait locus approach, we mapped modifier genes that can best explain the underlying phenotypic variation measured in our diverse population.
Results
Genetic analysis identified several loci associated with the variation in albuminuria and GFR, including a locus on the X chromosome associated with X inactivation and a locus on chromosome 2 containing Fmn1. Subsequent analysis of genetically reduced Fmn1 expression in Col4a5 knockout mice showed a decrease in albuminuria, podocyte effacement, and podocyte protrusions in the glomerular basement membrane, which support the candidacy of Fmn1 as a modifier gene for AS.
Conclusion
With this novel approach, we emulated the variability in the severity of kidney phenotypes found in human patients with Alport Syndrome through albuminuria and GFR measurements. This approach can identify modifier genes in kidney disease that can be used as novel therapeutic targets.
Lippincott Williams & Wilkins