Noninvasive Immunohistochemical Diagnosis and Novel MUC1 Mutations Causing Autosomal Dominant Tubulointerstitial Kidney Disease
Date
2018Author
Živná, MartinaKidd, Kendrah
Přistoupilová, Anna
Barešová, Veronika
DeFelice, Mathew
Blumenstiel, Brendan
Harden, Maegan
Conlon, Peter
Lavin, Peter
Connaughton, Dervla M.
Hartmannová, Hana
Hodaňová, Kateřina
Stránecký, Viktor
Vrbacká, Alena
Živný, Jan
Votruba, Miroslav
Sovová, Jana
Hůlková, Helena
Robins, Victoria
Perry, Rebecca
Wenzel, Andrea
Beck, Bodo B.
Seeman, Tomáš
Viklický, Ondřej
Rajnochová-Bloudíčková, Sylvie
Papagregoriou, Gregory
Deltas, Constantinos C.
Alper, Seth L.
Greka, Anna
Bleyer, Anthony J.
Kmoch, Stanislav
Vyleťal, Petr
ISSN
1046-66731533-3450
Source
Journal of the American Society of NephrologyVolume
29Issue
9Pages
2418-2431Google Scholar check
Metadata
Show full item recordAbstract
Visual Overview <img class="highwire-fragment fragment-image" alt="Figure1" src="https://jasn.asnjournals.org/content/jnephrol/29/9/2418/F1.medium.gif" width="440" height="320"/>Download figureOpen in new tabDownload powerpoint 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.