Universität zu Köln

Knaup, Karl X., Hackenbeck, Thomas, Popp, Bernt ORCID: 0000-0002-3679-1081, Stoeckert, Johanna, Wenzel, Andrea, Buettner-Herold, Maike, Pfister, Frederick, Schueler, Markus, Seven, Didem, May, Annette M., Halbritter, Jan, Groene, Hermann-Josef, Reis, Andre ORCID: 0000-0002-6301-6363, Beck, Bodo B., Amann, Kerstin, Ekici, Arif B. and Wiesener, Michael S. (2018). Biallelic Expression of Mucin-1 in Autosomal Dominant Tubulointerstitial Kidney Disease: Implications for Nongenetic Disease Recognition. J. Am. Soc. Nephrol., 29 (9). S. 2298 - 2310. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Knaup, Karl X. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hackenbeck, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Bernt UNSPECIFIED orcid.org/0000-0002-3679-1081 UNSPECIFIED Stoeckert, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenzel, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner-Herold, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfister, Frederick UNSPECIFIED UNSPECIFIED UNSPECIFIED Schueler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Seven, Didem UNSPECIFIED UNSPECIFIED UNSPECIFIED May, Annette M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Halbritter, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Groene, Hermann-Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Reis, Andre UNSPECIFIED orcid.org/0000-0002-6301-6363 UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Amann, Kerstin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ekici, Arif B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesener, Michael S. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-174081
DOI:	10.1681/ASN.2018030245
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	29
Number:	9
Page Range:	S. 2298 - 2310
Date:	2018
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EPITHELIAL MEMBRANE ANTIGEN; CLEAR-CELL CARCINOMA; TUMOR PROGRESSION; MUC1 MUTATION; UROMODULIN; PROTEIN; GENE; LOCALIZATION; POPULATION; ANEMIA Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17408