Endoplasmic reticulum-translocation is essential for APOL1 cellular toxicity.

Two variants at the gene, encoding apolipoprotein L1, account for more than 70% of the increased risk for chronic kidney disease in individuals of African ancestry. While the initiating event for APOL1 risk variant cell injury remains to be clarified, we explored the possibility of blocking APOL1 toxicity at a more upstream level. We demonstrate that deletion of the first six amino acids of exon 4 abrogates APOL1 cytotoxicity by impairing APOL1 translocation to the lumen of ER and splicing of the signal peptide.

APOL1-Mediated Cell Injury Involves Disruption of Conserved Trafficking Processes.

harbors C-terminal sequence variants (G1 and G2), which account for much of the increased risk for kidney disease in sub-Saharan African ancestry populations. Expression of the risk variants has also been shown to cause injury to podocytes and other cell types, but the underlying mechanisms are not understood. We used and to help clarify these mechanisms.