Hypercalciuria in Familial Hyperkalemia and Hypertension Accompanies Hyperkalemia and Precedes Hypertension: Description of a Large Family with the Q565E WNK4 Mutation

Mayan, Haim; Munter, Gabriel; Shaharabany, Miriam; Mouallem, Meir; Pauzner, Rachel; Holtzman, Eliezer J.; Farfel, Zvi

doi:10.1210/jc.2004-0037

Cited by 85 publications

(81 citation statements)

References 24 publications

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“…Moreover, considering phenotypes of Gitelman plus Bartter syndromes (DCTϩTAL salt-wasting hypokalemic alkalosis), it seems that the inverse of these may encompass hyperkalemia, acidosis, and lowrenin hypertension, all FHHt features. Other WNK4-FHHt features (e.g., degree of thiazide sensitivity, hypercalcuria [34]) might depend on the spectrum of overactivation within DCT-TAL. Clearly, this makes WNK4 expression in TAL of interest, but much needs to be clarified before a role in physiology or FHHt pathophysiology could be attributed.…”

Section: Discussionmentioning

confidence: 99%

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

O’Reilly¹,

Marshall²,

MacGillivray³

et al. 2006

Journal of the American Society of Nephrology

111

114

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T he role of WNK1 and WNK4 in control of electrolyte balance and BP first became apparent with their mutation being associated with familial hyperkalemic hypertension (FHHt; also known as Gordon syndrome and pseudohypoaldosteronism type 2), a human autosomal dominant disorder that features hypertension, hyperkalemia, and acidosis that usually are hyperresponsive to thiazide diuretics (1,2). FHHt can be caused by intronic deletions in WNK1 or missense mutations in WNK4 (3). Mutations in either cause a broadly similar phenotype, suggesting that WNK1 and WNK4 function in a common pathway. Unlike most monogenic disorders that affect BP, which feature reciprocal Na ϩ and K ϩ (and/or H ϩ ) imbalances and share a relationship to the aldosterone pathway (4), FHHt features concurrent NaCl and K ϩ (and/or H ϩ ) retention (1,3,5). This unusual characteristic indicates the existence of a novel "WNK pathway" functioning in normal physiology, which may allow the "independent of aldosterone" regulation of K and Na balance (and extracellular volume) by the kidney, ultimately also maintaining BP within the normal range. The BP-regulatory role of this WNK pathway is conserved in evolution as WNK1ϩ/Ϫ mice are hypotensive (6).Previously, we and others demonstrated that a 5Ј-truncated kinase-deficient isoform (WNK1-S) predominates in kidney (7), this being conserved between human and mouse (7-9). Isoform-specific probes distinguished ubiquitous low-level expression of full-length WNK1-long (WNK1-L) from abundant WNK1-S expression in distal nephron. Recent Xenopus oocyte studies implicate WNK4 in inhibition of NaCl reabsorption by thiazide-sensitive Na ϩ Cl Ϫ co-transporter (NCC) (10,11) and/or Materials and Methods Animal TreatmentAll procedures were carried out under provisions of ethically approved licenses and involved adult, 25-to 30-g, male C57BL/6 mice (Charles River, Margate, UK). Modified electrolyte feeds for mice were obtained from Special Diet Services (Witham, UK). RNA ExtractionAt conclusion of treatments of mice, both kidneys were removed under terminal anesthetic, immediately frozen on dry ice, and stored at Ϫ80°C. Frozen kidneys were fragmented and immediately homogenized in TRIzol Reagent (Invitrogen, Paisley, UK), and total RNA was extracted following the manufacturer's guidelines. Real-Time PCRAssays used ABI PRISM 7900 relative quantification real-time methods (Applied Biosystems, Foster City, CA). PCR was performed in 384-well plates (AB Gene) and used 10-l reactions that contained 5.0 l of TaqMan Master Mix (Applied Biosystems), 200 nM of each primer, 5 nM of probe, and 4.5 l of template (1:40 dilution of cDNA synthesized as described previously [7]). PCR conditions involved 95°C for 10 min, then 40 cycles of 95°C for 15 s and 60°C for 60 s. Standard template dilution curves enabled target gene quantification and normalization to the endogenous control TATA-Box Binding Protein (TBP). All group values were calibrated to their control groups.Validation studies using mouse renal RNA established TBP as an excelle...

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Section: Discussionmentioning

confidence: 99%

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

O’Reilly¹,

Marshall²,

MacGillivray³

et al. 2006

Journal of the American Society of Nephrology

111

114

View full text Add to dashboard Cite

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“…Patients with WNK1 mutations exhibit normocalciuria (2), whereas those with mutations in WNK4 manifest hypercalciuria (23). Mayan and colleagues, who correctly predicted constitutive overactivity of the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter in this syndrome before the elucidation of the molecular phenotype (23), recently proposed that mutant WNK4 causes hypercalciuria by influencing a Ca 2ϩ channel or transporter (22). A WNK4 and TRPV4 functional interaction may be perturbed in the setting of WNK4 mutation.…”

Section: Discussionmentioning

confidence: 99%

WNK kinases influence TRPV4 channel function and localization

Fu¹,

Subramanya²,

Rozansky³

et al. 2006

American Journal of Physiology-Renal Physiology

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, a renally expressed nonselective cation channel of the transient receptor potential (TRP) family, is gated by hypotonicity. Kinases of the WNK family influence expression and function of the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4. Along with TRPV4, WNK isoforms are highly expressed in the distal nephron. We show here that coexpression of WNK4 downregulates TRPV4 function in human embryonic kidney (HEK-293) cells and that this effect is mediated via decreased cell surface expression of TRPV4; total abundance of TRPV4 in whole cell lysates is unaffected. The effect of the related kinase WNK1 on TRPV4 function and surface expression was similar to that of WNK4. Disease-causing point mutations in WNK4 abrogate, but do not eliminate, the inhibitory effect on TRPV4 function. In contrast to wild-type WNK4, a kinase-dead WNK4 point mutant failed to influence TRPV4 trafficking; however, deletion of the entire WNK4 kinase domain did not blunt the effect of WNK4 on localization of TRPV4. Deletion of the extreme COOH-terminal putative coiled-coil domain of WNK4 abolished its effect. In immunoprecipitation experiments, we were unable to detect direct interaction between TRPV4 and either WNK kinase. In aggregate, these data indicate that TRPV4 is functionally regulated by WNK family kinases at the level of cell surface expression. Because TRPV4 and WNK kinases are coexpressed in the distal nephron in vivo and because there is a tendency toward hypercalcemia in TRPV4

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“…FHH patients carrying the WNK4 Q565E mutation exhibit hypercalciuria (22). Expression of WNK4 in the distal tubule (32) raises the possibility that WNK4 is a modulator of transcellular Ca 2ϩ transport, and WNK4 mutation may impair the normal Ca 2ϩ reabsorption in the distal tubule (21). Inasmuch as TRPV5 is a key player in the Ca 2ϩ transport pathway in the distal tubule, we examined whether TRPV5 could be regulated by WNK4 in the X. laevis oocyte expression system.…”

Section: Wnk4 Increased Trpv5-mediated Camentioning

confidence: 99%

“…Despite the aforementioned similarities in the two forms of FHH, there is a significant difference in Ca 2ϩ metabolism between FHH patients carrying WNK1 gene mutations and those carrying WNK4 gene mutations. Affected patients carrying the Q565E mutation in the WNK4 gene exhibit marked hypercalciuria compared with unaffected subjects in the same family (21,22). In contrast, in FHH patients with a WNK1 intronic deletion mutation, urinary Ca 2ϩ content is similar to that of the unaffected subjects (1).…”

mentioning

confidence: 97%

WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation ofWNK4

Jiang¹,

Ferguson²,

Peng³

2007

American Journal of Physiology-Renal Physiology

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uptake. The increase in Ca 2ϩ uptake was due to the increase in surface expression of TRPV5. When the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter NCC was coexpressed, the effect of WNK4 on TRPV5 was weakened by NCC in a dose-dependent manner. Although the WNK4 disease-causing mutants E562K, D564A, Q565E, and R1185C retained their ability to upregulate TRPV5, the blocking effect of NCC was further strengthened when wild-type WNK4 was replaced by the Q565E mutant, which causes FHH with hypercalciuria. We conclude that WNK4 positively regulates TRPV5-mediated Ca 2ϩ transport and that the inhibitory effect of NCC on this process may be involved in the pathogenesis of hypercalciuria of FHH caused by gene mutation in WNK4.epithelial calcium channel; CaT1; calcium reabsorption; WNK1; TRPV6 A NOVEL SERINE/THREONINE protein kinase family characterized by the absence of a conserved lysine residue in the kinase domain is formed by WNK [with no lysine (K)] kinases (34). Mutations in WNK1 and WNK4 genes, two members of the family of four WNK genes, which are linked to familial hyperkalemic hypertension (FHH, also known as pseudohypoaldosteronism type II or Gordon's syndrome) (32), highlight the physiological significance of these kinases. Mutations in WNK1 are deletions in the first intron, which result in overexpression of WNK1. Mutations in WNK4 are missense mutations, most of which are clustered in a small region rich in negatively charged amino acids after a coiled-coil stretch following its kinase domain, with the exception of R1185C, which is located close to the carboxy terminus. FHH patients carrying WNK1 or WNK4 mutations have common manifestations, including hyperkalemia, hypertension, mild metabolic acidosis, low renin, and normal glomerular filtration rate (1,22). Despite the aforementioned similarities in the two forms of FHH, there is a significant difference in Ca 2ϩ metabolism between FHH patients carrying WNK1 gene mutations and those carrying WNK4 gene mutations. Affected patients carrying the Q565E mutation in the WNK4 gene exhibit marked hypercalciuria compared with unaffected subjects in the same family (21,22). In contrast, in FHH patients with a WNK1 intronic deletion mutation, urinary Ca 2ϩ content is similar to that of the unaffected subjects (1).WNK4 has been shown to be a multifunctional protein regulating renal ion transport. WNK4 decreases activity of the thiazide-sensitive Na ϩ -Cl Ϫ cotransporter (NCC, also known as TSC and NCCT) (33, 36), the renal outer medullary K ϩ (ROMK) channel (16), and TRPV4, an osmolarity-sensitive Ca 2ϩ -permeable channel (7). On the other hand, WNK4 increases paracellular Cl Ϫ permeability, likely through phosphorylation of claudins (15, 35). The disease-causing Q565E mutant exhibits impaired ability to suppress NCC (36) and enhanced ability to suppress the ROMK channel (16). These findings explain the hypertension and hyperkalemia characteristic of FHH; however, the mechanism underlying hypercalciuria in patients carrying the Q565E mutation of the WNK4 gene is uncle...

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Hypercalciuria in Familial Hyperkalemia and Hypertension Accompanies Hyperkalemia and Precedes Hypertension: Description of a Large Family with the Q565E WNK4 Mutation

Cited by 85 publications

References 24 publications

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo

WNK kinases influence TRPV4 channel function and localization

WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation ofWNK4

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