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Chloride Transport across the Lysosomal Membrane
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Sonali Saha, Anja Blessing, Thomas J. Jentsch
Especially, the work on ClC-7 knockout mice changed the concepts of lysosomal ion homeostasis, including pH. The importance of lysosomal Clˉ/H+ exchange becomes obvious when considering the pathologies of Clcn7ˉ/ˉ mice. The loss of this transporter or its beta subunit Ostm1 in neurons leads to the accumulation of lysosomal storage material, resembling a special type of lysosomal storage disease, neuronal ceroid lipofuscinosis (Kasper et al., 2005; Wartosch et al., 2009). Newer studies from cells and kidneys allow the conclusion that a reduced lysosomal enzymatic activity and hence an impaired substrate degradation are at least in part causative for the accumulation of storage material (Chakraborty et al., 2017; Wartosch et al., 2009). So far, luminal pH was considered to be the major regulator of lysosomal enzyme activity (López-Otín and Bond, 2008; Turk et al., 2012), however, in various cell types derived from ClC-7 knockout mice, no pH defect was observed (Kasper et al., 2005; Steinberg et al., 2010; Weinert et al., 2014; Weinert et al., 2010), leading to the hypothesis that changed lysosomal [Clˉ] plays a major role in these pathologies (Jentsch, 2007; Smith and Schwappach, 2010). This conclusion was significantly bolstered by the analysis of Clcn5unc/unc (Novarino et al., 2010) and Clcn7unc/unc (Weinert et al., 2010) mice, in which point mutations converted the endosomal ClC-5 and lysosomal ClC-7 2Clˉ/H+-exchangers into pure Clˉ conductors. Although these should provide the countercurrent for vesicular acidification, as directly shown for ClC-5unc (Novarino et al., 2010), these mice displayed almost the same pathologies as the respective KOs. The severe underdevelopment of the acid-secreting ruffled border of Clcn7ˉ/ˉ osteoclasts (Kornak et al., 2001; Weinert et al., 2014), which is built up by lysosomal exocytosis, points to the role of ClC-7 in vesicular trafficking, as does the role of ClC-5 in renal endocytosis (Novarino et al., 2010).
Lowe syndrome with extremely short stature: growth hormone deficiency may be the pathogeny
Published in Growth Factors, 2019
Chengjun Dai, Liying Wang, Youli Li, Zhichao Zheng, Jieqi Qian, Chaoban Wang, Zishuo Liu, Xiaoou Shan
OCRL mutations were also discovered in Dent-2 disease (Recker, Reutter, and Ludwig 2013), while CLCN5 mutations were found in Dent-1 disease are CLCN5 mutations. The main manifestation of Dent-2 disease was renal tubular dysfunction including low molecular-weight proteinuria, hypercalciuria/nephrocalcinosis, phosphaturia, acidosis and glycosuria (Sugimoto et al. 2014). But few patients of Dent-2 disease had congenital cataracts or severe mental retardation (Recker, Reutter, and Ludwig 2013). Dent-2 disease was recognized to be a mild form of Lowe syndrome. Dr. Ankur Gupta et al. proposed that OCRL gene mutations in exons 8-23 were the cause of Lowe syndrome, while some frameshift mutations in exons 5-7 and missense mutations in exons 9–15 had a higher likelihood to cause Dent-2 disease (Gupta et al. 2010).
Plasma extracellular vesicle microRNAs for pulmonary ground-glass nodules
Published in Journal of Extracellular Vesicles, 2019
Jia-Tao Zhang, Hao Qin, Fiona Ka Man Cheung, Jian Su, Da-Dong Zhang, Shi-Yi Liu, Xiao-Fang Li, Jing Qin, Jun-Tao Lin, Ben-Yuan Jiang, Ri-Qiang Liao, Nie Qiang, Xue-Ning Yang, Hai-Yan Tu, Qing Zhou, Jin-Ji Yang, Xu-Chao Zhang, Ya-Nan Zhang, Yi-Long Wu, Wen-Zhao Zhong
miR-500a-3p, miR-501-3p, and miR-502-3p are proximally located in the intron of CLCN5 and are probably coregulated (Supplementary Figure 2C). These three miRNAs were upregulated in group 1 compared with those in group 2, with significant p values (p < 0.001, p < 0.001, and p < 0.001, respectively; Figure 5(c)). Intriguingly, the upregulation of these three miRNAs in tumor tissues from TCGA was associated with better overall survival than that observed in tumor tissues with the downregulation of these miRNAs (Figure 5(d)). Overall, the upregulation of these three miRNAs in the blood EVs of group 1 solid nodules was associated with improved prognosis in patients.