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