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J Am Soc Nephrol. 2018 Sep;29(9):2418-2431. doi: 10.1681/ASN.2018020180. Epub 2018 Jul 2.

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

Author information

1
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine.
2
Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
3
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Department of Nephrology, Beaumont Hospital, Dublin, Ireland.
5
Royal College of Surgeons, Dublin, Ireland.
6
Trinity Health Kidney Centre, Tallaght Hospital, Dublin, Ireland.
7
Institute of Pathophysiology, First Faculty of Medicine.
8
Institute of Pathology, First Faculty of Medicine, and.
9
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
10
Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
11
Department of Paediatrics, Second Faculty of Medicine, Charles University, Prague, Czech Republic.
12
Nephrology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
13
Molecular Medicine Research Center, Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus.
14
Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
15
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and.
16
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
17
Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, ableyer@wakehealth.edu.

Abstract

BACKGROUND:

Autosomal dominant tubulointerstitial kidney disease caused by mucin-1 gene (MUC1) mutations (ADTKD-MUC1) is characterized by progressive kidney failure. Genetic evaluation for ADTKD-MUC1 specifically tests for a cytosine duplication that creates a unique frameshift protein (MUC1fs). Our goal was to develop immunohistochemical methods to detect the MUC1fs created by the cytosine duplication and, possibly, by other similar frameshift mutations and to identify novel MUC1 mutations in individuals with positive immunohistochemical staining for the MUC1fs protein.

METHODS:

We performed MUC1fs immunostaining on urinary cell smears and various tissues from ADTKD-MUC1-positive and -negative controls as well as in individuals from 37 ADTKD families that were negative for mutations in known ADTKD genes. We used novel analytic methods to identify MUC1 frameshift mutations.

RESULTS:

After technique refinement, the sensitivity and specificity for MUC1fs immunostaining of urinary cell smears were 94.2% and 88.6%, respectively. Further genetic testing on 17 families with positive MUC1fs immunostaining revealed six families with five novel MUC1 frameshift mutations that all predict production of the identical MUC1fs protein.

CONCLUSIONS:

We developed a noninvasive immunohistochemical method to detect MUC1fs that, after further validation, may be useful in the future for diagnostic testing. Production of the MUC1fs protein may be central to the pathogenesis of ADTKD-MUC1.

KEYWORDS:

Autosomal Dominant Tubulo-Interstitial Kidney Disease; Inherited; MUC1; Mucin-1 Kidney Disease; diagnosis; immunostaining; kidney disease

PMID:
29967284
PMCID:
PMC6115665
DOI:
10.1681/ASN.2018020180
[Indexed for MEDLINE]
Free PMC Article

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