Allelic and Gene Dosage Effects Involving Uromodulin Aggregates Drive Autosomal Dominant Tubulointerstitial Kidney Disease

Missense mutations in theUMODgene encoding uromodulin cause autosomal dominant tubulointerstitial kidney disease (ADTKD), one of the most common monogenic kidney diseases. A pressing need for ADTKD is to bridge the gap between postulated gain-of-function mutations and organ damage - a prerequisite for therapeutic development. Based on two missenseUMODmutations associated with divergent progression of ADTKD, we generatedUmod^C171YandUmod^R186Sknock-in mice that showed strong allelic and gene dosage effects, with distinct dynamic pathways impacting on uromodulin trafficking, formation of intracellular aggregates, activation of ER stress, unfolded protein and immune responses, kidney damage and progression to kidney failure. Deletion of the wild-typeUmodallele in heterozygousUmod^R186Smice increased the formation of uromodulin aggregates and ER stress, indicating a protective role of wild-type uromodulin. Studies in kidney tubular cells confirmed biochemical differences between distinct uromodulin aggregates, with activation of specific quality control and clearance mechanisms. Enhancement of autophagy by starvation and mTORC1 inhibition decreased the uromodulin aggregates, suggesting a therapeutic strategy. These studies substantiate a model for allelic effects and the role of toxic aggregates in the progression of ADTKD-UMOD, with relevance for toxic gain-of-function mechanisms and for strategies to improve clearance of mutant uromodulin.