Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C

Choi, Keun Hee; Shin, Choong Ho; Yang, Sei Won; Cheong, Hae Il

doi:10.3345/kjp.2015.58.4.148

Cited by 12 publications

(17 citation statements)

References 15 publications

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“…Because it is known that increased NaCl reabsorption in the DCT is associated with decreased Ca 2+ absorption, 14 this mechanism not only claims the NaCl, but also further promotes hypercalciuria. The controversy of whether the thiazide effect on Ca 2+ excretion occurs directly in the DCTor elsewhere 62,63 does not contradict our findings.…”

Section: Discussioncontrasting

confidence: 62%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca excretion and NaCl reabsorption in response to extracellular Ca However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss. We used a combination of and models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well. Thiazide-sensitive Na uptake assays in oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC. Activation of CaSR can increase NCC activity the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca reabsorption, further promoting hypercalciuria.

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Section: Discussioncontrasting

confidence: 62%

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Bazúa‐Valenti

Rojas‐Vega

Castañeda‐Bueno

et al. 2018

JASN

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“…To date, five CaSR mutations have been identified in association with ADH1 and Bartter's syndrome and the clinical presentation and onset of Bartter's symptoms differ according to the type of mutation (Supplementary Table 1). The Lys29Glu and Tyr829Cys mutations are both associated with mild hypokalaemia and a late age of onset of 22 and 17 years, respectively (Vezzoli et al 2006, Choi et al 2015. Despite this, hypocalcaemia presents early and these patients develop signs of advanced hypocalcaemia including nephrocalcinosis and basal ganglia calcification.…”

Section: Adh1 With Bartter's Syndromementioning

confidence: 99%

Molecular and clinical insights from studies of calcium-sensing receptor mutations

Gorvin

2019

Journal of Molecular Endocrinology

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Twenty-five years have elapsed since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor is now recognized as a fundamental contributor to extracellular Ca 2+ (Ca 2+ e ) homeostasis, regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C G-protein-coupled receptor (GPCR) that is functionally active as a homodimer and couples to multiple G-protein subtypes to activate intracellular signalling pathways. The importance of the CaSR in the regulation of Ca 2+ e has been highlighted by the identification of >400 different germline loss-and gain-of-function CaSR mutations that give rise to disorders of Ca 2+ e homeostasis. CaSR-inactivating mutations cause neonatal severe hyperparathyroidism, characterised by marked hypercalcaemia, skeletal demineralisation and failure to thrive in early infancy; and familial hypocalciuric hypercalcaemia, an often asymptomatic disorder associated with mild-moderately elevated serum calcium concentrations. Activating mutations are associated with autosomal dominant hypocalcaemia, which is occasionally associated with a Bartter's-like phenotype. Recent elucidation of the CaSR extracellular domain structure enabled the locations of CaSR mutations to be mapped and has revealed clustering in locations important for structural integrity, receptor dimerisation and ligand binding. Moreover, the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. This review presents the current understanding of the genetic landscape of CaSR mutations by summarising findings from clinical and functional studies of diseaseassociated mutations. It concludes with reflections on how recently uncovered signalling pathways may expand the understanding of calcium homeostasis disorders.

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“…There is a subgroup of five activating mutants of the CASR that in addition to hypocalcemia and relative hypercalciuria lead to renal loss of sodium, chloride, and magnesium, which results in hyperreninemia, hyperaldosteronism, hypokalemia, and metabolic alkalosis, a disease called Bartter's syndrome type 5 (BS type 5) (29,30,31,32,33,34). These patients usually are already symptomatic as infants or children, but some patients continue into adulthood with relatively little symptoms (31).…”

Section: Mutations Causing Gain Of Casr Functionmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper-or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper-and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C

Cited by 12 publications

References 15 publications

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway

Molecular and clinical insights from studies of calcium-sensing receptor mutations

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

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