PDF(Pubmed)
Abstract：
Dent disease type 1 is characterized by pathogenic CLCN5 gene variants and impaired receptor-mediated endocytosis in proximal tubules. However, mutation-related abnormalities in proximal tubules have not yet been described. Here, we present three patients with CLCN5 alterations and distinct morphological changes of the apical endocytic-lysosomal apparatus. The proximal tubular ultrastructure was investigated in kidney biopsy samples of three boys genotyped for non-nephrotic proteinuria. Controls: seven patients with nephrotic-range glomerular proteinuria. The genotyping findings revealed an already-known missense mutation in one patient and hitherto undescribed frameshift variants in two patients. Low-molecular-weight proteinuria, focal global glomerulosclerosis, proximal tubular changes, and tubular calcium deposits characterized each case. Three subsets of proximal tubular cells were observed: those without any abnormality, those with aplasia of apical endocytic-lysosomal apparatus and shrinkage of cells, and those with hypoplasia of apical endocytic apparatus, accumulation of proteinaceous substance in dysmorphic lysosomes, and dysmorphic mitochondria. The distribution of subsets varied from patient to patient. In one patient with a frameshift variant, an oxidative stress-like injury of proximal tubular cells and podocytes accompanied the above-mentioned alterations. Focal aplasia/hypoplasia of apical endocytic apparatus and subsequent changes in cytoplasmic organelles characterized proximal tubules in the CLCN5 pathogenic variants.
摘要：
1型Dent疾病的特征是致病性CLCN5基因变体和近端小管中受体介导的内吞作用受损。然而,尚未描述近端小管中与突变相关的异常。这里,我们介绍了3例CLCN5改变和顶端胞吞-溶酶体装置明显的形态学改变的患者。在三个非肾病性蛋白尿基因分型的男孩的肾活检样本中研究了近端肾小管超微结构。对照：7例肾病范围肾小球蛋白尿患者。基因分型的发现揭示了一名患者中已知的错义突变，而两名患者中迄今未描述的移码变异。低分子量蛋白尿，局灶性全球肾小球硬化，近端肾小管改变,和管状钙沉积物表征每种情况。观察到三个近端肾小管细胞亚群：没有任何异常，根尖内吞-溶酶体体发育不全和细胞收缩的人，根尖内吞器官发育不全的人，蛋白质物质在异形溶酶体中的积累，和畸形线粒体。子集的分布因患者而异。在一个移码变种的病人中，近端肾小管细胞和足细胞的氧化应激样损伤伴随着上述改变。在CLCN5致病变体中，根尖内吞器官的局灶性发育不全/发育不全以及随后的细胞质细胞器变化以近端小管为特征。
