Mechanisms and relevance of the Mucin 1-associated autosomal dominant tubulointerstitial kidney disease

• Applicant: Professor Dr. Michael Wiesener
• Subject Area: Nephrology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279970103

Autosomal Dominant Tubulointerstitial Kidney Diseases (ADTKD) primarily lead to tubular atrophy and interstitial fibrosis, with renal failure usually occurring between the 3rd and 6th decade of life. ADTKD is caused by mutations in at least one of four different genes: UMOD, HNF1B, REN and, as recently described, MUC1, but the clinical manifestations of each gene defect are largely indistinguishable. The pathogenesis of the different diseases remains largely unknown, but may stem from the distal parts of the renal tubular apparatus. Unraveling the molecular mechanisms of these disorders is likely to provide significant insight into the pathogenesis of tubulointerstitial fibrosis, which is a hallmark of virtually all types of kidney disease. To date, it is completely unclear what the prevalence of the disease may be, since it appears highly likely that most cases remain unrecognized. In this research proposal we will focus on the MUC1-associated disease, since this is the most recently identified variant with least knowledge and since we have been working on numerous large MUC1-families in the past. Mucin 1 is a transmembrane mucoprotein with a large extracellular domain, which consists of up to 125 repetitive elements of 20 amino acids (Variable Number of Tandem Repeats, VNTR). Mucin 1 is expressed in the distal tubular apparatus of the kidney, where its physiological function may be a protective barrier formation against infectious and toxic pathogens. The sole mutation of MUC1 described so far is an insertion of a single nucleotide in the VNTR with a frameshift effect and an early termination after the VNTR domain. However, any routine analysis on the VNTR is hampered by its very high GC content and the repetitive structure. Thus, we may well miss a number of MUC1 families to date. It is not known whether this mutation is a loss or gain of function mutation, yet different hints may point to the latter. We have access to approximately 20 families with ADTKD, collected historical kidney biopsies and generated MUC1-frameshift antibodies and expression plasmids, which will be critical to perform the prospected work.We will carefully study the physiological expression of Mucin 1 in the kidney, as well as its frameshift protein in patient material. In view of the difficult genetic diagnosis we will further attempt to develop non-genomic tests to analyse the frameshift protein of MUC1. We will aim to clarify the pathogenesis of the MUC1-associated disease, both in cell culture and in mouse models. The families collected to date will be studied in detail for their individual VNTR and the underlying mutation, as well as attempt to clarify the so far undiagnosed families. Finally, we will analyse a large cohort of 5000 kidney patients for the prevalence of ADTKD in this cohort. These studies should profoundly help to improve the diagnosis and understanding of the disease, which may well have relevance to kidney diseases in general.

• DFG Programme: Research Grants
• Co-Investigators: Professorin Dr. Kerstin Amann; Professor Dr. Kai-Uwe Eckardt; Professor Dr. André Reis