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2015 ; 128
(24
): 4550-9
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Screen-based identification and validation of four new ion channels as regulators
of renal ciliogenesis
#MMPMID26546361
Slaats GG
; Wheway G
; Foletto V
; Szymanska K
; van Balkom BW
; Logister I
; Den Ouden K
; Keijzer-Veen MG
; Lilien MR
; Knoers NV
; Johnson CA
; Giles RH
J Cell Sci
2015[Dec]; 128
(24
): 4550-9
PMID26546361
show ga
To investigate the contribution of ion channels to ciliogenesis, we carried out a
small interfering RNA (siRNA)-based reverse genetics screen of all ion channels
in the mouse genome in murine inner medullary collecting duct kidney cells. This
screen revealed four candidate ion channel genes: Kcnq1, Kcnj10, Kcnf1 and Clcn4.
We show that these four ion channels localize to renal tubules, specifically to
the base of primary cilia. We report that human KCNQ1 Long QT syndrome disease
alleles regulate renal ciliogenesis; KCNQ1-p.R518X, -p.A178T and -p.K362R could
not rescue ciliogenesis after Kcnq1-siRNA-mediated depletion in contrast to
wild-type KCNQ1 and benign KCNQ1-p.R518Q, suggesting that the ion channel
function of KCNQ1 regulates ciliogenesis. In contrast, we demonstrate that the
ion channel function of KCNJ10 is independent of its effect on ciliogenesis. Our
data suggest that these four ion channels regulate renal ciliogenesis through the
periciliary diffusion barrier or the ciliary pocket, with potential implication
as genetic contributors to ciliopathy pathophysiology. The new functional roles
of a subset of ion channels provide new insights into the disease pathogenesis of
channelopathies, which might suggest future therapeutic approaches.