Repression of ferritin light chain translation by human eIF3

Abstract

AbstractA central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5’ untranslated region (5’-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are thought to disrupt translation repression by altering iron regulatory protein (IRP) interactions with theFTLmRNA 5’-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor ofFTLmRNA translation, and eIF3-mediatedFTLrepression is disrupted by a subset of SNPs inFTLthat cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.