Novel pathogenic variants in CUBN uncouple proteinuria from renal function.
Novel pathogenic variants in CUBN uncouple proteinuria from renal function.
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DOI：
10.1186/s12967-022-03706-y
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发表时间：
2022-10-20
影响因子：
7.4
通讯作者：
Li, Qiu
中科院分区：
文献类型：
--
作者：
Gan, Chun;Zhou, Xindi;Chen, Dan;Chi, Huan;Qiu, Jiawen;You, Hui;Chen, Yaxi;Wang, Mo;Yang, Haiping;Jiang, Wei;Li, Qiu
蛋白尿是慢性肾脏疾病（CKD）中一种与肾脏和心血管疾病风险高度相关的不利临床状况。然而，是否所有的蛋白尿形式都与肾脏损害有关尚不清楚。Cubilin是一种在肾近端小管中高度表达的内吞受体，介导白蛋白、转铁蛋白和α - 1微球蛋白的摄取。外显子组测序法初步鉴定了候选基因。随着外显子组测序结合Sanger测序的应用，我们通过生物信息学分析进一步关注CUBN。通过临床样本、HEK293T细胞系体外实验以及小鼠体内实验，对临床数据进行互补分析，并系统表征变异的表达和功能，验证了潜在致病变异的致病作用。在这项研究中，我们在两个家族中发现了四个位于Cubilin维生素B12 （vitB12）结合域(由CUBN编码，NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T （p.R2266X), c.6821 + 3A > G和c.5153_5154delCT (p.S1718X)）之后的新变异。此外，这些变异严重影响Cubilin在肾近端小管的表达和功能，引起蛋白尿、尿转铁蛋白和α1微球蛋白水平升高，但没有进行性肾小球滤过屏障（GFB）损伤、维生素b12缺乏或血液中HDL和白蛋白水平异常。进一步的机制研究表明，CUBN的vitb12结合域后的变异仅仅破坏了与无羊膜（AMN）的关联，表现出异常定位于细胞质而不是细胞膜。在这里，我们的研究结果表明，CUBN的vitb12结合区域后的不同突变类型使肾小球滤过屏障的蛋白尿分离，这可能是人类意想不到的常见良性疾病，可能不需要任何降蛋白尿治疗或肾活检。在线版本包含补充材料，可在10.1186/s12967-022-03706-y获得。
Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin. Exome sequencing method initially identified candidate genes. With the application of exome sequencing combined with Sanger sequencing, we further focused on CUBN through bioinformatics analysis. The pathogenic effects of the potentially causative variants were verified utilizing complementary analysis of clinical data and systematic characterization of the variants’ expression and function with clinical samples and in vitro experiments in HEK293T cell lines along with in vivo experiments in mice. In this study, we identified four novel variants locating after the vitamin B12 (vitB12)-binding domain of Cubilin (encoded by CUBN, NM_001081.3: c.4397G > A (p.C1466Y), c.6796C > T (p.R2266X), c.6821 + 3A > G and c.5153_5154delCT (p.S1718X)) in two families. Moreover, the variants severely affected the expression and function of Cubilin in renal proximal tubules and caused albuminuria, increasing levels in urine transferrin and α1-microglobulin, but without progressive glomerular filtration barrier (GFB) impairment, vitB12 deficiencies or abnormal blood levels of HDL and albumin. Further mechanistic insights showed that the variants after the vitB12-binding domain of CUBN merely disrupted the association with Amnionless (AMN) that exhibited aberrant localization in cell cytoplasm rather than membrane. Here, our findings suggested that different mutation types after the vitB12-binding domain of CUBN uncouple proteinuria from glomerular filtration barrier, that may be an unexpectedly common benign condition in humans and may not require any proteinuria-lowering treatment or renal biopsy. The online version contains supplementary material available at 10.1186/s12967-022-03706-y.
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影响因子：
13.6
作者：
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