Mutations in the transcription factor LMX1B have been identified as the cause of the autosomal-dominant disease nail-patella syndrome. It manifests in small or absent patellae and dysplastic or missing toe- and fingernails, but the prognosis of the patients is determined by the development of renal symptoms due to dysfunctional podocytes. The pathogenetic mechanisms leading to podocyte damage and their association with specific mutations in the LMX1B gene are not understood, which has impeded the development of specific therapeutic strategies. Here we identify the pathogenetic mechanism affecting many patients with nail-patella syndrome, provide proof of principle for a novel therapeutic approach and suggest a domain-specific effect in gene regulation by LMX1B. Interestingly, missense mutations in the LIM domains of Lmx1b result in a recessive phenotype in two different knock-in mouse lines due to proteasomal degradation of the mutated proteins. The decreased half-life of the mutated LMX1B proteins can be attributed to ubiquitinylation and is prolonged by two proteasomal inhibitors, one of which was also tested in our mouse models and results in an alleviation of the renal symptoms. RNA sequencing of genetically altered podocytes indicates that LMX1B predominantly acts as a transcriptional repressor and furthermore suggests that the two LIM domains contribute to the distinct regulation of LMX1B target genes. We conclude that proteasomal inhibitors, drugs already approved for treatment of patients with multiple myeloma, warrant further studies to prevent renal failure in patients with nail-patella syndrome caused by mutations in the LIM domains. These studies should be designed to deliver the drug specifically to podocytes and to target specific ubiquitin ligases in order to limit side effects.