Autosomal Tubulointerstitial Kidney Disease—MUC1 Type: Differential Proteomics Suggests that Mutated MUC1 (insC) Affects Vesicular Transport in Renal Epithelial Cells

Abstract

Autosomal dominant tubulointerstitial kidney disease associated to the MUC1 gene (ADTKD-MUC1; formerly MCKD1) belongs to a heterogeneous group of rare hereditary kidney diseases that is prototypically caused by frameshift mutations in the MUC1 repeat domain. The mutant MUC1 (insC) lacks the transmembrane domaine, exhibits aberant cellular topology, and hence might gain a function during the pathological process. To get insight into potential pathomechanisms we perform differential proteomics of extracellular vesicles shed by renal epithelia into the urine of patients. The study is based on three ADTKD patients and individual controls applying iTRAQ/LC-MS/MS. A total of 796 proteins were identified across all biological and technical replicates, and 298 proteins were quantified. A proportion of 47 proteins were fold-changed species. GO Term Enrichment analysis revealed proteins with significantly changed expression in ADTKD-associated extracellular vesicles as vesicular transport-associated proteins. Among these VTA1 is involved in the endosomal multivesicular body pathway associated with transport to lysosomes or export via exosomes. VTA1 is also claimed to play roles as a cofactor of the AAA ATPases VPS4A and VPS4B in the disassembly of ESCRT III. Protein interaction databases list VPS4B, CHMP2A, and IST1 as VTA1 binding partners. (Data are available via ProteomeXchange with identifier PXD008389.).

Weighted Gene Co-expression Network Analysis Reveals Different Immunity but Shared Renal Pathology Between IgA Nephropathy and Lupus Nephritis

“…Furthermore, urinary exosomal miR-135b-5p, miR-107, and miR-31 produced mainly by renal tubular cells were correlated with the prognosis of LN (Garcia-Vives et al, 2020). In accordance with the upregulated hub genes identified in our study, EPCAM and MUC1 were strongly expressed on the renal tubular epithelium and were assumed to contribute to tubulointerstitial lesion formation (Staubach et al, 2018;Hagiyama et al, 2019). All evidence support that the upregulated DGEs in purple module might play a transport role via the extracellular vesicle pathway and participate in the pathological changes in the renal tubules in IgAN and LN.…”

Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease

“…10 For this reason, it has been hypothesized that the specific MUC1fs produced by the cytosine duplication is critical to the pathogenesis of ADTKD-MUC1. 3,11 It has been postulated that there may be other, distinct MUC1 mutations that produce the same MUC1fs and result in ADTKD-MUC1. A family with a deletion of 2 bp before the VNTR, resulting in the same MUC1fs protein, has also been reported.…”

A dynamic mucin mRNA signature associates with COVID-19 disease presentation and severity

“…Of particular interest is the strong correlation between mortality, renal failure, and MUC1 mRNA expression and between mechanical ventilation and MUC4 and MUC16 mRNA expression. It is noteworthy that in autosomal dominant tubulointerstitial kidney disease, renal failure is also associated with aberrant MUC1 expression ( 26 ). Expression of several mucins is also negatively correlated with the highest ferritin levels found in the sera and the presence of fungal coinfection, more specifically an Aspergillus fumigatus infection, during ICU stays.…”