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.

Broad Institute of Harvard and Massachusetts Institute of Technology Cambridge Massachusetts

Center for Molecular Medicine Cologne University of Cologne Cologne Germany

Department of Medicine Brigham and Women's Hospital Boston Massachusetts; and

Department of Medicine Harvard Medical School Boston Massachusetts

Department of Nephrology Beaumont Hospital Dublin Ireland

Department of Paediatrics 2nd Faculty of Medicine Charles University Prague Czech Republic

Division of Nephrology and Vascular Biology Research Center Beth Israel Deaconess Medical Center Boston Massachusetts

Institute of Human Genetics University Hospital of Cologne Cologne Germany

Institute of Pathology 1st Faculty of Medicine and

Institute of Pathophysiology 1st Faculty of Medicine

Molecular Medicine Research Center Department of Biological Sciences University of Cyprus Nicosia Cyprus

Nephrology Department Institute for Clinical and Experimental Medicine Prague Czech Republic

Research Unit for Rare Diseases Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine

Royal College of Surgeons Dublin Ireland

Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina

Trinity Health Kidney Centre Tallaght Hospital Dublin Ireland

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J Am Soc Nephrol. 2020 Apr;31(4):892. doi: 10.1681/ASN.2020010083. PubMed

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