Characterization of the neoprotein MUC1-fs in patient-derived cells with ADTKD-MUC1

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous group of diseases that regularly lead to kidney failure in mid adulthood. In ADTKD-MUC1 a distinct neoprotein generated by a frameshift mutation, MUC1-fs, is pathogenic and accumulates in distal renal tubular cells. However, the pathomechanism of the disease and the regulation of the MUC1-fs are poorly understood. Primary tubular cells from the urine of several probands were established and immortalized. The length of the repeat region of both alleles of MUC1, as well as the mutated repeat localization were precisely defined by long range sequencing. The pathogenic MUC1-fs is readily detectable in patient-derived cells and has a considerably longer half-life than the wild-type mucin 1. Targeting the secretory pathway with BRD4780, a compound previously reported as putatively therapeutic, leads to downregulation of MUC1-fs in each of our patient-derived cell model. However, wild-type mucin 1 and numerous other transcriptional pathways were also affected by BRD4780, thus being rather unselective. Tubular cells derived from the urine appear to be a suitable model to analyze the pathogenic MUC1-fs of an individual patient, enabling pharmacological studies of novel therapies.