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@ARTICLE{Wojciechowski:856622,
      author       = {Wojciechowski, Daniel and Kovalchuk, Elena and Yu, Lan and
                      Tan, Hua and Fahlke, Christoph and Stölting, Gabriel and
                      Alekov, Alexi K.},
      title        = {{B}arttin {R}egulates the {S}ubcellular {L}ocalization and
                      {P}osttranslational {M}odification of {H}uman {C}l-/{H}+
                      {A}ntiporter {C}l{C}-5},
      journal      = {Frontiers in physiology},
      volume       = {9},
      issn         = {1664-042X},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {FZJ-2018-05989},
      pages        = {1490},
      year         = {2018},
      abstract     = {Dent disease 1 (DD1) is a renal salt-wasting tubulopathy
                      associated with mutations in the Cl-/H+ antiporter ClC-5.
                      The disease typically manifests with proteinuria,
                      hypercalciuria, nephrocalcinosis, and nephrolithiasis but is
                      characterized by large phenotypic variability of no clear
                      origin. Several DD1 cases have been reported lately with
                      additional atypical hypokalemic metabolic alkalosis and
                      hyperaldosteronism, symptoms usually associated with another
                      renal disease termed Bartter syndrome (BS). Expression of
                      the Bartter-like DD1 mutant ClC-5 G261E in HEK293T cells
                      showed that it is retained in the ER and lacks the complex
                      glycosylation typical for ClC-5 WT. Accordingly, the mutant
                      abolished CLC ionic transport. Such phenotype is not unusual
                      and is often observed also in DD1 ClC-5 mutants not
                      associated with Bartter like phenotype. We noticed,
                      therefore, that one type of BS is associated with mutations
                      in the protein barttin that serves as an accessory subunit
                      regulating the function and subcellular localization of
                      ClC-K channels. The overlapping symptomatology of DD1 and
                      BS, together with the homology between the proteins of the
                      CLC family, led us to investigate whether barttin might also
                      regulate ClC-5 transport. In HEK293T cells, we found that
                      barttin cotransfection impairs the complex glycosylation and
                      arrests ClC-5 in the endoplasmic reticulum. As barttin and
                      ClC-5 are both expressed in the thin and thick ascending
                      limbs of the Henle’s loop and the collecting duct,
                      interactions between the two proteins could potentially
                      contribute to the phenotypic variability of DD1. Pathologic
                      barttin mutants differentially regulated trafficking and
                      processing of ClC-5, suggesting that the interaction between
                      the two proteins might be relevant also for the
                      pathophysiology of BS. Our findings show that barttin
                      regulates the subcellular localization not only of kidney
                      ClC-K channels but also of the ClC-5 transporter, and
                      suggest that ClC-5 might potentially play a role not only in
                      kidney proximal tubules but also in tubular kidney segments
                      expressing barttin. In addition, they demonstrate that the
                      spectrum of clinical, genetic and molecular pathophysiology
                      investigation of DD1 should be extended.},
      cin          = {ICS-4},
      ddc          = {610},
      cid          = {I:(DE-Juel1)ICS-4-20110106},
      pnm          = {551 - Functional Macromolecules and Complexes (POF3-551)},
      pid          = {G:(DE-HGF)POF3-551},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000448008900001},
      pubmed       = {pmid:30405442},
      doi          = {10.3389/fphys.2018.01490},
      url          = {https://juser.fz-juelich.de/record/856622},
}