Proteasome inhibition alleviates proteinuria in Lmx1b knock-in mice with dysfunctional LIM domains

We have generated two knock-in mouse lines which carry missense mutations in the LIM domains of LMX1B and thus mimic the situation in patients. Surprisingly, both mouse lines only developed a phenotype in the recessive state.

This is due to the misfolding of the respective LIM domains, in which a zinc-chelating amino acid was exchanged by an alternative amino acid, and the subsequent ubiquitin-dependent proteasomal degradation of mutant LMX1B. The proteasomal inhibitors bortezomib and MG132 stabilized the mutant proteins in vitro. A therapeutic study demonstrated that bortezomib markedly reduced podocyte damage and alleviated proteinuria in adult mice with a floxed and a knock-in Lmx1b allele.