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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Among intracellular ClC channels, only ClC5 and ClC7 have been associated with human diseases. ClC5 is highly expressed in proximal tubular cells of the kidney where it regulates the uptake of albumin and low-molecular-weight proteins. Dysfunction of ClC5 leads to Dent disease, a rare X-linked recessive nephropathy characterized by excessive urinary loss of small proteins, increased levels of Ca2+ in the urine, kidney calcifications and kidney stones (Fisher et al., 1994; Steinmeyer et al., 1995; Wrong et al., 1994). Subcellularly, ClC5 is located in early endosomes of proximal tubular cells where it plays a role in endocytosis by supporting efficient endosomal acidification by a mechanism independent of endosomal acidification (Novarino et al., 2010; Smith and Lippiat, 2010).
Iron metabolism and chronic inflammation in IgA nephropathy
Published in Renal Failure, 2023
Zhang-yu Tian, Zhi Li, Ling Chu, Yan Liu, Jin-rong He, Yu Xin, Ai-mei Li, Hao Zhang
The renal reabsorption of Tf and iron plays an important role in iron regulation in the renal tubular epithelial system [11,12,51]. It has been shown that renal tubular dysfunction, as observed in patients with Fanconi syndrome, Dent disease and Lowe syndrome, results in reduced reabsorption [12,52,53]. Thus, renal tubular dysfunction can increase urinary Tf and iron excretion. In the glomeruli, transferrin-bound iron (TBI) can enter mesangial cells and endothelial cells via TfR1 and podocytes via an as yet unidentified transporter [11]. A limited iron-transferrin complex can be bound to TfR1 and megalin-cubilin complexes on the parietal membrane of proximal tubular epithelial cells by mediating the endocytosis of transferrin [54]. In addition, TfR1 and NGALR, which are correlated with apical membrane TBI uptake, are also expressed in the distal convoluted tubules and collecting ducts, respectively [55]. NTBI is currently considered as the main contributor to the pathology of iron-overload disorders [37,38]. Renal uptake of NTBI has been demonstrated in human and mouse proximal tubule cell lines and in distal tubule segments [51,56,57]. Therefore, the alteration of NTBI in kidney disease and the relationship with renal ferroptosis deserve to be noticed.
Usefulness of functional splicing analysis to confirm precise disease pathogenesis in Diamond-Blackfan anemia caused by intronic variants in RPS19
Published in Pediatric Hematology and Oncology, 2021
Satoru Takafuji, Takeshi Mori, Noriyuki Nishimura, Nobuyuki Yamamoto, Suguru Uemura, Kandai Nozu, Kiminori Terui, Tsutomu Toki, Etsuro Ito, Hideki Muramatsu, Yoshiyuki Takahashi, Masafumi Matsuo, Tomohiko Yamamura, Kazumoto Iijima
Recently, we examined the pathogenicity of reported intronic variants located outside obvious splicing consensus sequences, within two bases immediately before and after exons (AG and GT), in some inherited kidney diseases including in Alport syndrome and Dent disease.25,26 In these reports, hybrid minigene analysis was useful for assessing whether the variant in question causes aberrant splicing. The results of the present study suggest that in vitro functional analysis using hybrid mini gene constructs may be useful for estimating the pathogenicity of novel intronic variants, especially those located outside splice consensus sequences, in the field of inherited hematological disorders.