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.

背景造成的粘蛋白1基因（常染色体显性小管间质性肾病MUC1）突变（ADTKD- MUC1）的特征在于渐进肾衰竭。对ADTKD- MUC1的遗传评估专门测试了产生独特移码蛋白（MUC1fs）的胞嘧啶重复。我们的目标是开发免疫组织化学方法，以检测由胞嘧啶复制和可能的其他移码突变产生的MUC1fs，并在MUC1fs蛋白免疫组化染色呈阳性的个体中鉴定新的MUC1突变。

方法我们对来自ADTKD- MUC1阳性和阴性对照的尿细胞涂片和各种组织以及来自已知ADTKD基因突变为阴性的37个ADTKD家族的个体进行了尿细胞涂片和各种组织的MUC1fs免疫染色。我们使用新颖的分析方法来识别MUC1移码突变。

结果改良技术后，尿细胞涂片对MUC1fs免疫染色的敏感性和特异性分别为94.2％和88.6％。对17个MUC1fs免疫染色阳性的家族进行的进一步基因测试显示，六个家族具有5个新的MUC1移码突变，均预测相同MUC1fs蛋白的产生。

结论我们开发了一种无创免疫组织化学方法来检测MUC1fs，经过进一步验证，该方法可能在将来用于诊断测试。MUC1fs蛋白的产生可能是ADTKD- MUC1发病机理的中心。