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

LMX1B codes for a transcription factor of the LIM-homeodomain family, mutations in this gene cause the autosomal-dominant hereditary disease nail-patella syndrome. 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. RNA sequencing of isolated podocytes from those mice revealed a number of genes which were up- or down-regulated in both knock-in mouse lines but also led to the identification to genes whose regulation specifically depended on the LIM-B domain. Our data provide proof of principle for a therapeutic strategy in patients with nail-patella syndrome suffering from missense mutations in the LIM domains of LMX1B