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J Am Soc Nephrol. 2018 Sep;29(9):2298-2309. doi: 10.1681/ASN.2018030245. Epub 2018 Jul 26.

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

Author information

1
Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
2
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
3
Institute of Human Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
4
Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
5
Cerrahpaşa Medical Faculty, Department of Medical Biology, Istanbul University, Istanbul, Turkey.
6
Institute for Surgical Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
7
Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany.
8
Department of Cellular and Molecular Pathology, Deutsches Krebsforschungszentrum Heidelberg, Heidelberg, Germany.

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.

KEYWORDS:

CKD; IF/TA; MCKD; TIN; interstitial nephritis

Comment in

PMID:
30049680
PMCID:
PMC6115663
DOI:
10.1681/ASN.2018030245
[Indexed for MEDLINE]
Free PMC Article

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