Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition

Knaup K, Hackenbeck T, Popp B, Stoeckert J, Wenzel A, Büttner-Herold M, Pfister F, Schüler M, Seven D, May AM, Halbritter J, Gröne HJ, Reis A, Beck BB, Amann KU, Ekici AB, Wiesener MS (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Journal of the American Society of Nephrology American Society of Nephrology

DOI: 10.1681/ASN.2018030245

Abstract

BACKGROUND: Providing the correct diagnosis for patients with tubulointerstitial kidney disease and secondary degenerative disorders, such as hypertension, remains a challenge. The autosomal dominant tubulointerstitial kidney disease (ADTKD) subtype caused by MUC1 mutations (ADTKD-MUC1) is particularly difficult to diagnose, because the mutational hotspot is a complex repeat domain, inaccessible with routine sequencing techniques. Here, we further evaluated SNaPshot minisequencing as a technique for diagnosing ADTKD-MUC1 and assessed immunodetection of the disease-associated mucin 1 frameshift protein (MUC1-fs) as a nongenetic technique. METHODS: We re-evaluated detection of MUC1 mutations by targeted repeat enrichment and SNaPshot minisequencing by haplotype reconstruction via microsatellite analysis in three independent ADTKD-MUC1 families. Additionally, we generated rabbit polyclonal antibodies against MUC1-fs and evaluated immunodetection of wild-type and mutated allele products in human kidney biopsy specimens. RESULTS: The detection of MUC1 mutations by SNaPshot minisequencing was robust. Immunostaining with our MUC1-fs antibodies and an MUC1 antibody showed that both proteins are readily detectable in human ADTKD-MUC1 kidneys, with mucin 1 localized to the apical membrane and MUC1-fs abundantly distributed throughout the cytoplasm. Notably, immunohistochemical analysis of MUC1-fs expression in clinical kidney samples facilitated reliable prediction of the disease status of individual patients. CONCLUSIONS: Diagnosing ADTKD-MUC1 by molecular genetics is possible, but it is technically demanding and labor intensive. However, immunohistochemistry on kidney biopsy specimens is feasible for nongenetic diagnosis of ADTKD-MUC1 and therefore, a valid method to select families for further diagnostics. Our data are compatible with the hypothesis that specific molecular effects of MUC1-fs underlie the pathogenesis of this disease.

Authors with CRIS profile

Karl Knaup Department of Medicine 4 – Nephrology and Hypertension Bernt Popp Institute of Human Genetics Maike Büttner-Herold Department of Nephropathology Markus Schüler Department of Medicine 4 – Nephrology and Hypertension André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Kerstin Ute Amann Department of Nephropathology Arif Bülent Ekici Institute of Human Genetics

Involved external institutions

Universität zu Köln DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Universität Leipzig DE Germany (DE) Box Hill Hospital - Eastern Health AU Australia (AU)

How to cite

APA:

Knaup, K., Hackenbeck, T., Popp, B., Stoeckert, J., Wenzel, A., Büttner-Herold, M.,... Wiesener, M.S. (2018). Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition. Journal of the American Society of Nephrology. https://doi.org/10.1681/ASN.2018030245

MLA:

Knaup, Karl, et al. "Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition." Journal of the American Society of Nephrology (2018).

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