Decreased Transcriptional Activity of<i>Calcium-sensing receptor</i>Gene Promoter 1 Is Associated With Calcium Nephrolithiasis

Vezzoli, Giuseppe; Terranegra, Annalisa; Aloia, Andrea; Arcidiacono, Teresa; Milanesi, Luciano; Mosca, Ettore; Mingione, Alessandra; Spotti, D.; Cusi, Daniele; Hou, Jianghui; Hendy, Geoffrey N.; Soldati, Laura

doi:10.1210/jc.2013-1834

Cited by 50 publications

(45 citation statements)

References 39 publications

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“…However, in a previous study, no functional difference was observed between wild-type and the Arg990Gly CaSR variant (21). More recently, Vezzoli et al reported that the minor G allele of CASR SNP rs6776158, located in the promoter region of CASR, occurred more frequently in stone formers than in controls (69). Unexpectedly in this context, this allele was reported to decrease, rather than increase, CASR expression.…”

Section: Is Casr Involved In the Pathogenesis Of Hypercalciuria?mentioning

confidence: 86%

Calcium Sensing in the Renal Tubule

2015

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Section: Is Casr Involved In the Pathogenesis Of Hypercalciuria?mentioning

confidence: 86%

Calcium Sensing in the Renal Tubule

2015

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“…Another study mapping the CaSR gene regulatory region observed the association of a SNP (rs6776158) sited within the promoter 1 with calcium stones. The minor allele at this SNP was shown to reduce the promoter 1 transcriptional activity in two renal cell models [28]. …”

Section: The Casr Genementioning

confidence: 99%

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

et al. 2014

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Background: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. Summary: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randall's plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randall's plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and -phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium-oxalate stones by triggering cellular mechanisms that lead to the Randall's plaque formation. © 2014 S. Karger AG, Basel

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“…These studies showed either no association with allelic CASR variants (27, 28, 33), minor effects on the tested outcomes (25, 27, 34), or non-replicable results, which may be related to genetic heterogeneity of the tested populations (26, 27, 32, 35). More recently, we tested the association of rare allelic variants in 40 genes associated with urinary calcium excretion in 960 well-characterized individuals, including CASR (36).…”

Section: The Role Of Casr In Human Diseasementioning

confidence: 98%

“…Recent genetic population studies investigated the association of allelic CASR variants with various common diseases, including kidney stones (25), hypertension (26), coronary heart disease (27), diabetes mellitus (27), bone mineral density (28), Alzheimer disease (29), epilepsy (30), pancreatitis (31) and various cancers (27, 32). These studies showed either no association with allelic CASR variants (27, 28, 33), minor effects on the tested outcomes (25, 27, 34), or non-replicable results, which may be related to genetic heterogeneity of the tested populations (26, 27, 32, 35).…”

Section: The Role Of Casr In Human Diseasementioning

confidence: 99%

New functional aspects of the extracellular calcium-sensing receptor

Toka

2014

Current Opinion in Nephrology and Hypertension

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Purpose of review Variations in extracellular calcium level have a large impact on kidney function. Most of the effects seen are attributed to the calcium-sensing receptor (CaSR), a widely expressed G-protein-coupled cell surface protein with important function in bone mineral homeostasis. The purpose of this review is to recapitulate novel functional aspects of CaSR. Recent findings Results from mouse models surmise important functions for CaSR in various tissues. In the kidney, the main role of CaSR is the regulation of calcium reabsorption in the thick ascending limb, independently of its role on parathyroid hormone secretion. CaSR modulates claudin 14, the gatekeeper of paracellular ion transport in the thick ascending limb that is associated with urinary calcium excretion. One intracellular signaling pathway by which CaSR alters tight junction permeability is the calcineurin-NFAT1c-microRNA-claudin14 axis. Summary The main function of CaSR in the kidney is the regulation of calcium excretion in the thick ascending limb, independently of parathyroid hormone. CaSR modulates paracellular cation transport by altering expression of the tight junction protein claudin 14. Still more work is needed to fully understand all functions of CaSR in the kidney. Alternative pathways of calcium “sensing” in the kidney need to be investigated.

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Decreased Transcriptional Activity ofCalcium-sensing receptorGene Promoter 1 Is Associated With Calcium Nephrolithiasis

Abstract: Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Cited by 50 publications

References 39 publications

Calcium Sensing in the Renal Tubule

Calcium Sensing in the Renal Tubule

Idiopathic Calcium Nephrolithiasis: A Review of Pathogenic Mechanisms in the Light of Genetic Studies

New functional aspects of the extracellular calcium-sensing receptor

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