A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34426578.
- Also identified by DOI 10.1038/s41467-021-25377-x and PMC identifier 8382756.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Genome-wide association studies (GWAS) have identified loci for kidney disease, but the causal variants, genes, and pathways remain unknown. Here we identify two kidney disease genes Dipeptidase 1 (DPEP1) and Charged Multivesicular Body Protein 1 A (CHMP1A) via the triangulation of kidney function GWAS, human kidney expression, and methylation quantitative trait loci. Using single-cell chromatin accessibility and genome editing, we fine map the region that controls the expression of both genes. Mouse genetic models demonstrate the causal roles of both genes in kidney disease. Cellular studies indicate that both Dpep1 and Chmp1a are important regulators of a single pathway, ferroptosis and lead to kidney disease development via altering cellular iron trafficking.
Medical subject headings
- Dipeptidases
- Ferroptosis
- Genetic Loci
- Genetic Predisposition to Disease
- Kidney Diseases
- Vesicular Transport Proteins