Department of Pediatrics, Albert Szent-Györgyi Medical School and Health Center, University of Szeged, 6720 Szeged, Hungary.
Department of Pediatrics, University of Pécs, 7624 Pécs, Hungary.
Int J Mol Sci. 2024 Jan 12;25(2):966. doi: 10.3390/ijms25020966.
Dent disease type 1 is characterized by pathogenic 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 pathogenic variants.
Dent 病 1 型的特征是致病性基因变异和近端肾小管中受体介导的内吞作用受损。然而，近端肾小管中与突变相关的异常尚未被描述。在这里，我们介绍了 3 名具有 CLCN5 改变和顶端内吞体-溶酶体装置形态变化明显的患者。对 3 名经基因分型为非肾病范围蛋白尿的男孩的肾活检样本进行了近端管状超微结构研究。对照组：7 名肾病范围肾小球蛋白尿患者。基因分型结果显示，1 名患者存在已知的错义突变，2 名患者存在以前未描述的移码变异。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是每个病例的特征。观察到三种不同的近端肾小管细胞亚群：无任何异常的细胞、顶端内吞体-溶酶体装置发育不全和细胞萎缩的细胞以及顶端内吞体发育不全、异常溶酶体中蛋白物质积累和异常线粒体的细胞。亚群的分布在患者之间有所不同。在一名带有移码变异的患者中，近端肾小管细胞和足细胞发生了类似于氧化应激的损伤，伴有上述改变。顶端内吞装置的局灶性发育不全/发育不良以及随后的细胞质细胞器改变是致病变异中近端肾小管的特征。
