Novel &lt;i&gt;SLC12A3&lt;/i&gt; Mutations in Chinese Patients with Gitelman’s Syndrome

Shao, Leping; Ren, Hong; Wang, Weiming; Zhang, Wen; Feng, Xiaopei; Li, Xiao; Chen, Nan

doi:10.1159/000117815

Cited by 36 publications

(52 citation statements)

References 35 publications

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“…The novel variants are seven missense mutations (p.C146F, p.T304M, p.N359D, p.T465P, p.P556L, p.N611T, and p.Y857C), a deletion of a guanine (c.402delG) that caused a frameshift that resulted in a truncated polypeptide with 141 acid residues (p.Arg135AlafsX8), and a splice mutation (c.964C2TOC), which was confirmed to lead to a shorter transcript characterized as skipping exon 7 by cDNA sequencing (p.Ala285 ArgfsX48). Additionally, seven mutations (p.T60M, p.G439S, p.S555L, p.R655C, p.R928C, p.Thr114A-lafsX142, and p.Arg959SerfsX11) identified in this study had been reported previously (8,10,(14)(15)(16)(17)(18)(19)(20). To both patients suspected of PA and GS, patient 1 showed compound heterozygosity for mutations of p.T60M and p.T304M, patient 2 was also a compound heterozygote with variants of p.T465P and p.N611T.…”

Section: Resultssupporting

confidence: 76%

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Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Zhang¹,

Gao²,

Bindels³

et al. 2009

European Journal of Endocrinology

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Background: Primary aldosteronism (PA) is the most common form of secondary hypertension, while Gitelman's syndrome (GS) is the most common inherited renal tubular disease. However, coexistence of these two diseases has never been previously reported. Aim and subjects: The aim of our study was to describe the association of GS and PA in two unrelated patients and compare their clinical presentation with a group of patients with GS. Methods: Ten subjects suspected to have only GS were assigned to the control group. Saline infusion test was used to confirm the diagnosis of PA. GS was confirmed by sequencing of the causal genes (SLC12A3 and CLCNKB) and functional analyses in Xenopus laevis oocytes. Results: Confirmatory tests, gene analysis, and functional studies demonstrated the coexistence of GS and PA in both patients. In total, nine novel SLC12A3 gene variants, including seven missense mutations, one splice mutation, and one frameshift deletion, were found in 12 subjects. Four mutations (p.T60M, p.T304M, p.T465P, and p.N611T) harbored by the two patients with both PA and GS were revealed to be loss-of-function variants. Although both patients were normotensive, neither of them had normal nocturnal dip. Conclusions: Two rare diseases GS and PA may occasionally coexist in one subject. In these patients, salt depletion and volume constriction might explain the absence of hypertension normally seen in PA patients. However, the protective mechanism against hypertension via down-regulation of renal sodium handling was probably not sufficient in those patients, since their normal circadian rhythm of blood pressure was disrupted.

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Section: Resultssupporting

confidence: 76%

“…SLC12A3 and CLCNKB genes were analyzed as described (8,9). To analyze transcriptional profiles for the SLC12A3-splicing mutations, we extracted total RNA from blood using TRIzol (Invitrogen/Gibco).…”

Section: Mutation Analysismentioning

confidence: 99%

Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Zhang¹,

Gao²,

Bindels³

et al. 2009

European Journal of Endocrinology

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“…that ablates the key SPAK-OSR1 phosphorylation site in NCC is frequently detected in Asian patients with Gitelman's syndrome (Lin et al, 2005;Maki et al, 2004;Shao et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways

Richardson

Sakamoto

Heros

et al. 2011

Journal of Cell Science

159

174

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Ion cotransporters, such as the Na+/Cl− cotransporter (NCC), control renal salt re-absorption and are regulated by the WNK-signalling pathway, which is over-stimulated in patients suffering from Gordon's hypertension syndrome. Here, we study the regulation of the NKCC2 (SLC12A1) ion cotransporter that contributes towards ~25% of renal salt re-absorption and is inhibited by loop-diuretic hypertensive drugs. We demonstrate that hypotonic low-chloride conditions that activate the WNK1-SPAK and OSR1 pathway promote phosphorylation of NKCC2 isoforms (A, B and F) at five residues (Ser91, Thr95, Thr100, Thr105 and Ser130). We establish that the SPAK and OSR1 kinases activated by WNK interact with an RFQV motif on NKCC2 and directly phosphorylate Thr95, Thr100, Thr105 and, possibly, Ser91. Our data indicate that a SPAK-OSR1-independent kinase, perhaps AMP-activated protein kinase (AMPK), phosphorylates Ser130 and that phosphorylation of Thr105 and Ser130 plays the most important roles in stimulating NKCC2 activity. In contrast with NCC, whose membrane translocation is triggered by SPAK-OSR1 phosphorylation, NKCC2 appears to be constitutively at the membrane. Our findings provide new insights into how NKCC2 is regulated and suggest that inhibitors of SPAK and/or OSR1 for the treatment of hypertension would be therapeutically distinct from thiazide or loop diuretics, as they would suppress the activity of both NCC and NKCC2.

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“…Moreover, the Thr60Ala mutation also markedly suppressed phosphorylation of Thr46 and Thr55, which indicates that phosphorylation of Thr60 is essential for enabling and/or maintaining the phosphorylation of other residues (Richardson et al, 2008). The importance of Thr60 in mediating NCC activation is further highlighted by the discovery of a Thr60Met NCC mutation in Asian patients with Gitelman's syndrome (Lin et al, 2005;Maki et al, 2004;Shao et al, 2008). The Thr60Met mutation in NCC might be more prevalent in Asian populations, because it has so far not been reported in other ethnic groups with Gitelman's syndrome (Ji et al, 2008).…”

Section: T Yeh Ya N Stqp Ge Prkvrp Tl a DL Hsf Lk Qe A Yeh Ya N Salp mentioning

confidence: 98%

The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

Richardson

Alessi

2008

Journal of Cell Science

271

323

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It has recently been shown that the WNK [with-no-K(Lysand NKCC2, which are targets for the commonly used bloodpressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.

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Novel <i>SLC12A3</i> Mutations in Chinese Patients with Gitelman’s Syndrome

Cited by 36 publications

References 35 publications

Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways

The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway

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