Diversity in the Sorting Disorder Induced by the Mutant CIC-5 Chloride Channels Responsible for Dent's Disease
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概要
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A number of mutations in the CLCN5 gene have been demonstrated as causative genes linked to Dent's disease. However, the interrelation between cytoplasmic sorting and loss function of each CIC-5 mutant is still unclear. To elucidate how the mutation in CLCN5 affects the frafficking of its gene product, we focused on the identification of subcellular localization of the mutant channels using an in vitro heterologous expression system on CHO-K1 cultured cells. There naturally occurring ClC-5 mutations related to Dent's disease, one missense type (S270R) and two frameshift in C-terminus types (658delC and 2079/2080insA) resulting in truncation of the protein, were examined in detail. Among three CLCN5 mutations the 2079/2080insA frameshift mutation is newly identified in this study. As a result, S270R missense mutant reach the early endosomes, but do not function normally. In contrast, the other two mutants with frameshift in C-terminus are retained in the endoplasmic reticulum (ER) thus failing to reach the destination site, the early endosomes. Collectively, these findings suggest that the structural modifications in the loop between helices H and I (S270R) affect the function of the ClC-5 channel rather than the intracellular sorting, and that the Cterminus distal to Leu693, with disrupting CBS2 domain, contains a specific region vital for the proper sorting of the ClC-5 protein from the ER to the physiological destination site. To our knowledge, this study is the first that elucidates the diversity of the sorting disorder in the mutants related to Dent's disease using the same expression system comparatively.
- 北里大学の論文
- 2003-08-31
著者
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Inoue Satoko
Shigei Medical Research Institute
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Inoue S
Divisions Of Ultrastructural Biology Shigei Medical Research Institute
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HIGASHIHARA Masaaki
Department of Hematology, Kitasato University School of Medicine
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Higashihara Masaaki
Fourth Department Of Internal Medicine Kitasato University School Of Medicine
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Higashihara Masaaki
あけぼの病院 内科
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Higashihara Masaaki
Section Of Hematology Fourth Department Of Internal Medicine Kitasato University School Of Medicine
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Higashihara Masaaki
北里大学 医学部第4内科(血液内科)
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Naito Ichiro
Shigei Med. Res. Inst., Okayama Univ. Grad. Sch. Med. and Dent.
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Sakamoto Hisato
Fourth Department of Internal Medicine, Kitasato University School of Medicine
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Matsuo Takatoshi
Fourth Department of Internal Medicine, Kitasato University School of Medicine
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Kobayashi Yutaka
Fourth Department of Internal Medicine, School of Medicine, Kitasato University
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Higashihara Masaaki
Fourth Department Of Internal Medicine School Of Medicine Kitasato University
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Sakamoto Hisato
Fourth Department Of Internal Medicine Kitasato University School Of Medicine
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Matsuo Takatoshi
Fourth Department Of Internal Medicine Kitasato University School Of Medicine
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Kobayashi Yutaka
Department Of Internal Medicine Akebono Hospital
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Inoue Satoko
Shigei Medical Res. Inst.
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