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:
CreatorsEmailORCIDORCID Put Code
Knaup, Karl X.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hackenbeck, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Popp, BerntUNSPECIFIEDorcid.org/0000-0002-3679-1081UNSPECIFIED
Stoeckert, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wenzel, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner-Herold, MaikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, FrederickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schueler, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seven, DidemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, Annette M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Halbritter, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Groene, Hermann-JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reis, AndreUNSPECIFIEDorcid.org/0000-0002-6301-6363UNSPECIFIED
Beck, Bodo B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Amann, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ekici, Arif B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesener, Michael S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
EPITHELIAL MEMBRANE ANTIGEN; CLEAR-CELL CARCINOMA; TUMOR PROGRESSION; MUC1 MUTATION; UROMODULIN; PROTEIN; GENE; LOCALIZATION; POPULATION; ANEMIAMultiple languages
Urology & NephrologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17408

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