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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},
}