Hereditary Renal Cell Carcinomas (RCC) are caused by mutations in predisposing genes, the major ones including VHL, FLCN, FH and MET. However, many families with inherited RCC have no germline mutation in these genes. Using Whole Exome Sequencing on germline DNA from a family presenting three different histological renal tumors (an angiomyolipoma, a clear-cell RCC and an oncocytic papillary RCC), we identified a frameshift mutation in the Neighbor of BRCA1 gene 1 (NBR1), segregating with the tumors. NBR1 encodes a cargo receptor protein involved in autophagy. Genetic and functional analyses suggested a pathogenic impact of the mutation. Indeed, functional study performed in renal cell lines showed that the mutation alters NBR1 interactions with some of its partners (such as p62/SQSTM1), leading to a dominant negative effect. This results in an altered autophagic process and an increased proliferative capacity in renal cell lines. Our study suggests that NBR1 may be a new predisposing gene for RCC, however its characterization needs to be further investigated in order to confirm its role in renal carcinogenesis.

遗传性肾细胞癌 (RCC) 是由易感基因突变引起的，主要包括VHL、FLCN、FH和MET。然而，许多遗传性 RCC 家族在这些基因中没有种系突变。对来自呈现三种不同组织学肾肿瘤（血管平滑肌脂肪瘤、透明细胞 RCC 和嗜酸细胞乳头状 RCC）的家族的种系 DNA 使用全外显子组测序，我们在BRCA1基因 1的邻居（NBR1）中发现了移码突变，与肿瘤。丁腈橡胶1编码参与自噬的货物受体蛋白。遗传和功能分析表明突变的致病影响。事实上，在肾细胞系中进行的功能研究表明，该突变改变了 NBR1 与其一些伙伴（如 p62/SQSTM1）的相互作用，导致显性负效应。这导致肾细胞系的自噬过程发生改变和增殖能力增加。我们的研究表明NBR1可能是 RCC 的一个新的易感基因，但其特征需要进一步研究以证实其在肾癌发生中的作用。