TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways
TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways
复制标题
DOI：
10.1016/j.ajhg.2018.12.016
复制
发表时间：
2019-02-07
影响因子：
9.8
通讯作者：
Antignac, Corinne
中科院分区：
文献类型：
--
作者：
Dorval, Guillaume;Kuzmuk, Valeryia;Antignac, Corinne
激素抵抗型肾病综合征(SRNS)的特征是大量蛋白尿，最常见的是局灶性和节段性肾小球硬化(FSGS)。导致SRNS的基因突变的鉴定提高了我们对疾病机制的理解，并突出了足细胞的缺陷，足细胞是一种高度专业化的肾小球上皮细胞，是疾病发病机制的主要因素。通过外显子测序，我们在两个X连锁早发性SRNS伴FSGS的家系中发现了TBC1D8B的错义突变。TBC1D8B是一种未知的Rab-GTP酶激活蛋白，可能参与内吞和循环途径。免疫荧光研究显示，人肾小球中存在TBC1D8B，受影响的单个足细胞表现出与FSGS中常见的迁移缺陷相关的结构变化。在斑马鱼中，我们证明了独特的TBC1D8B直系同源基因引起的蛋白尿的敲除和敲除，并且这种表型可以被人TBC1D8B mRNA注射拯救，但不能被这两个突变的mRNAs中的任何一个拯救。我们还发现了TBC1D8B和Rab11b之间的相互作用，Rab11b是细胞中囊泡循环的关键蛋白。有趣的是，在受影响的个体的足细胞和成纤维细胞中，内化和再循环过程都显著减少，证实了TBC1D8B在细胞再循环过程中的关键作用，可能是作为Rab11b GTP酶激活蛋白。总之，这些结果证实了TBC1D8B的致病变异参与了X连锁足细胞病变，并指出循环过程的改变是SRNS的一种机制。
Steroid-resistant nephrotic syndrome (SRNS) is characterized by high-range proteinuria and most often focal and segmental glomerulosclerosis (FSGS). Identification of mutations in genes causing SRNS has improved our understanding of disease mechanisms and highlighted defects in the podocyte, a highly specialized glomerular epithelial cell, as major factors in disease pathogenesis. By exome sequencing, we identified missense mutations in TBC1D8B in two families with an X-linked early-onset SRNS with FSGS. TBC1D8B is an uncharacterized Rab-GTPase-activating protein likely involved in endocytic and recycling pathways. Immunofluorescence studies revealed TBC1D8B presence in human glomeruli, and affected individual podocytes displayed architectural changes associated with migration defects commonly found in FSGS. In zebrafish we demonstrated that both knockdown and knockout of the unique TBC1D8B ortholog-induced proteinuria and that this phenotype was rescued by human TBC1D8B mRNA injection, but not by either of the two mutated mRNAs. We also showed an interaction between TBC1D8B and Rab11b, a key protein in vesicular recycling in cells. Interestingly, both internalization and recycling processes were dramatically decreased in affected individuals' podocytes and fibroblasts, confirming the crucial role of TBC1D8B in the cellular recycling processes, probably as a Rab11b GTPase-activating protein. Altogether, these results confirmed that pathogenic variations in TBC1D8B are involved in X-linked podocytopathy and points to alterations in recycling processes as a mechanism of SRNS.