Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function
Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function
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DOI：
10.1172/jci129937
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发表时间：
2020-01-01
影响因子：
15.9
通讯作者：
Simons, Matias
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文献类型：
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作者：
Bedin, Mathilda;Boyer, Olivia;Simons, Matias
背景蛋白尿被认为是一种不利的临床条件，加速肾脏和心血管疾病。然而，目前尚不清楚是否所有形式的蛋白尿都是有害的。CUBN的突变导致Imerslund-Grasbeck综合征（IGS），其特征是肠道对维生素B12的吸收不良，在某些情况下是蛋白尿。CUBN编码cubilin，一种肠和近端肾小管摄取受体，含有27个用于配体结合的CUB结构域。我们使用新一代肾脏疾病基因测序技术对疑似遗传性肾脏疾病和慢性蛋白尿患者进行基因分型。使用生物信息学、结构建模和流行病学方法分析CUBN变体。我们确定了39例患者，其中CUBN基因的双等位基因致病变异与慢性孤立性蛋白尿和儿童早期发病相关。由于这些患者的蛋白尿中蛋白尿的比例很高，肾小球疾病，如类固醇耐药型肾病综合征或Alport综合征往往是主要的临床诊断，促使肾活检和使用蛋白尿降低治疗。然而，所有病例的肾功能均正常。相比之下，我们没有发现任何双等位基因CUBN变异蛋白尿患者肾功能下降或局灶节段性肾小球硬化症。与更多的N-末端IGS突变不同，41个蛋白尿相关的CUBN变体中有37个导致维生素B12结合结构域后的修饰或截短。最后，我们在对大量人群的荟萃分析中发现4种C-末端CUBN变异与蛋白尿和GFR轻度升高相关。总的来说，我们的数据表明，在肾脏白蛋白重吸收的cubilin的C-末端的一半的重要作用。由于cubilin功能降低导致的白蛋白尿可能是人类中意外常见的良性疾病，可能不需要任何降低蛋白尿的治疗或肾活检。
BACKGROUND. Proteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Grasbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODS. We used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTS. We identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSION. Collectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.