The role of biased calcium-sensing receptor signalling in urinary calcium excretion and kidney stone disease

2019 ◽  
Author(s):  
Michelle Goldsworthy ◽  
Asha Bayliss ◽  
Anna Gluck ◽  
Akira Wiberg ◽  
Benjamin Turney ◽  
...  
Keyword(s):  
Kidney Stone ◽  
Urinary Calcium ◽  
Stone Disease ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Kidney Stone Disease ◽  
Receptor Signalling ◽  
Calcium Sensing

scholarly journals High Urinary Calcium Excretion and Genetic Susceptibility to Hypertension and Kidney Stone Disease

2006 ◽  
Vol 17 (9) ◽  
pp. 2567-2575 ◽  
Author(s):  
Andrew Mente ◽  
R. John D’ A. Honey ◽  
John M. McLaughlin ◽  
Shelley B. Bull ◽  
Alexander G. Logan
Keyword(s):  
Genetic Susceptibility ◽  
Kidney Stone ◽  
Urinary Calcium ◽  
Stone Disease ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Kidney Stone Disease

Biased calcium-sensing receptor signalling in the pathogenesis of kidney stone disease

2021 ◽  
Vol 79 ◽  
pp. S329
Author(s):  
M. Goldsworthy ◽  
A. Wiberg ◽  
B.W. Turney ◽  
D. Furniss ◽  
R.V. Thakker ◽  
...  
Keyword(s):  
Kidney Stone ◽  
Stone Disease ◽  
Calcium Sensing Receptor ◽  
Kidney Stone Disease ◽  
Receptor Signalling ◽  
Calcium Sensing

scholarly journals SINGLE-NUCLEOTIDE POLYMORPHISMS OF CALCIUM-SENSING RECEPTOR ENCODING GENE ASSOCIATED WITH CALCIUM KIDNEY STONE DISEASE IN BABYLON PROVINCE

2018 ◽  
Vol 11 (2) ◽  
pp. 417 ◽  
Author(s):  
Zahraa Isam ◽  
Rabab Omran ◽  
Ammad Hassan Mahmood
Keyword(s):  
Amino Acid ◽  
Single Nucleotide Polymorphisms ◽  
Kidney Stone ◽  
Stone Disease ◽  
Control Group ◽  
Nucleotide Polymorphisms ◽  
Calcium Sensing Receptor ◽  
Single Nucleotide ◽  
Kidney Stone Disease ◽  
Calcium Sensing

  Objective: The calcium-sensing receptor (CASR) is a G-protein-coupled receptor that is mainly expressed in the parathyroid and the kidneys where it regulates parathyroid hormone secretion and renal tubular calcium reabsorption. Inactivating and activating CASR gene due to mutations severally caused hypercalcemia or hypocalcemia disorders. The aim of the study was to investigate the risk factor of CASR rs1801725 (Ala986Ser) patients with renal disease.Method: The blood samples were collected from 100 patients and divided into two groups, each one containing 50 samples; chronic kidney disease and end-stage renal disease, who admitted Merjan Teaching Hospital in Babylon Province, Iraq, from February to July 2016. In addition, healthy persons as a control group (50 samples). Genotyping of CASR single-nucleotide polymorphisms (SNP) was performed using a polymerase chain reaction technique, followed by single-strand conformation polymorphism. Accordingly, these DNA polymorphisms were confirmed using DNA sequencing.Results: The conformational haplotypes of CASR, exon7 NCBI Primer3plus reference were obtained in three patterns, including two, three, and four bands, due to the presence SNPs within the studied region. These SNPs leads to change three amino acid residues of CASR, including amino acid substitutions were Ala 128→ Ser 128, Leu 155→Tye 155, and Leu 156→ Ser 156 that may affect or modified the tertiary structure of the receptor, subsequently the function like the affinity to calcium ion may be effected.Conclusion: These results suggest that the variants of CASR SNP, namely, rs1801725 might be involved in susceptibility to kidney stone disease.

scholarly journals The role of biased calcium-sensing receptor signalling in urinary calcium excretion and kidney stone disease

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Michelle Goldsworthy
Keyword(s):  
Calcium Concentration ◽  
Urinary Calcium ◽  
Fold Change ◽  
Urinary Calcium Excretion ◽  
Maximal Response ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Serum Calcium Concentration ◽  
University Of Oxford ◽  
Calcium Sensing

Michelle Goldsworthy1,2, Asha Bayliss2, Anna Gluck2, Akira Wiberg3, Benjamin Turney1, DominicFurniss3, Rajesh Thakker2, Sarah Howles1,2 1Nuffield Department of Surgical Sciences, University of Oxford, United Kingdom.2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, UnitedKingdom.3Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Universityof Oxford, United Kingdom.   Nephrolithiasis is a major health burden with a poorly understood pathogenesis. We conducted a genome-wide association study in British and Japanese populations identifying twenty nephrolithiasis-associated loci. Mutations in the calcium-sensing receptor (CaSR) cause disorders of calcium homeostasis and five identified loci (DGKD, DGKH, WDR72, GPIC1 and BCR) were predicted to influence CaSR-signalling. In a validation population, we demonstrated that genotype at the DGKD-associated locus correlated with urinary calcium excretion but not serum calcium concentration. In vitro studies demonstrated that knockdown and overexpression of DGKD resulted in biased CaSR-signalling. Thus, treatment of CaSR-expressing HEK cells with DGKD-targeted siRNA (DGKD-KD), resulted in decreased MAPK responses to alterations in extracellular calcium concentration [Ca2+]e, as assessed by SRE-reporter and ERK-phosphorylation (pERK) assays, when compared to cells treated with scrambled siRNA (WT) but without alteration in intracellular calcium responses [Ca2+]i as assessed by NFAT-reporter and Fluo-4 calcium assays (SRE maximal response DGKD-KD =5.28 fold change vs. WT=7.20 p=0.0065, pERK maximal response DGKD-KD=24.77, vs. WT= 39.46 fold change, p=0.0056). Conversely, DGKD overexpression (DGKD-OE) increased MAPK responses but suppressed [Ca2+]i responses to alterations in [Ca2+]e (SRE maximal response DGKD-OE =14.13 fold change vs. WT=9.06 fold change, p=0.01; NFAT maximal response DGKD-OE=13.67 fold change vs WT=59.16 fold change, p=0.0001). Our results demonstrate that alterations in DGKD expression cause biased CaSR-signalling. This biased signalling may provide an explanation for the correlation of genotype at the DGKD-associated locus with urinary calcium excretion but not serum calcium concentration. Our findings suggest that biased CaSR-signalling may be a common cause of nephrolithiasis.

scholarly journals A Novel Variant in the Calcium-Sensing Receptor Associated with Familial Hypocalciuric Hypercalcemia and Low-to-Normal PTH

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Sachin K. Majumdar ◽  
Tess Jacob ◽  
Allen Bale ◽  
Allison Bailey ◽  
Jeffrey Kwon ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Novel Variant

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by mild elevations in serum calcium and relatively low urinary calcium excretion. It results from an elevated set point in serum calcium arising from variants in the calcium-sensing receptor (CaSR) gene but also AP2S1 and GNA11 genes, which encode for adaptor-related protein complex 2 and G11 proteins, respectively. The manifestations of FHH can vary and sometimes overlap with primary hyperparathyroidism making the diagnosis challenging. Case Presentations. We report a mother and daughter with a novel heterozygous variant in the CaSR gene resulting in a serine to leucine substitution at position 147 (S147L) of the CaSR. Both patients had mild hypercalcemia, relatively low urinary calcium excretion, elevated calcitriol, and low-to-normal intact PTH. The proband (daughter) presented with symptoms associated with hypercalcemia and was incidentally found to have a bony lesion suspicious for osteitis fibrosa cystica, and she was also diagnosed with sarcoidosis. Subtotal parathyroidectomy revealed normal-weight parathyroid glands comprised of 50–80% parathyroid epithelial cells, which has been documented as within the spectrum of normal. Her mother had no symptoms, and no intervention was pursued. Conclusion. We report a novel variant in the CaSR associated with FHH in two patients with similar biochemical features yet differing clinical manifestations. While the relationship of the bony findings and parathyroid histology with this variant remains unclear, these cases enrich our knowledge of CaSR physiology and provide further examples of how varied the manifestations of FHH can be.

scholarly journals The role of biased calcium-sensing receptor signalling in urinary calcium excretion and kidney stone disease

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Michelle Goldsworthy
Keyword(s):  
Calcium Concentration ◽  
Urinary Calcium ◽  
Fold Change ◽  
Urinary Calcium Excretion ◽  
Maximal Response ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Serum Calcium Concentration ◽  
University Of Oxford ◽  
Calcium Sensing

Michelle Goldsworthy1,2, Asha Bayliss2, Anna Gluck2, Akira Wiberg3, Benjamin Turney1, DominicFurniss3, Rajesh Thakker2, Sarah Howles1,2 1Nuffield Department of Surgical Sciences, University of Oxford, United Kingdom.2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, UnitedKingdom.3Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Universityof Oxford, United Kingdom. Nephrolithiasis is a major health burden with a poorly understood pathogenesis. We conducteda genome-wide association study in British and Japanese populations identifying twentynephrolithiasis-associated loci. Mutations in the calcium-sensing receptor (CaSR) causedisorders of calcium homeostasis and five identified loci (DGKD, DGKH, WDR72, GPIC1 and BCR)were predicted to influence CaSR-signalling. In a validation population, we demonstrated that genotype at the DGKD-associated locuscorrelated with urinary calcium excretion but not serum calcium concentration. In vitro studiesdemonstrated that knockdown and overexpression of DGKD resulted in biased CaSR-signalling.Thus, treatment of CaSR-expressing HEK cells with DGKD-targeted siRNA (DGKD-KD), resulted indecreased MAPK responses to alterations in extracellular calcium concentration [Ca2+]e, asassessed by SRE-reporter and ERK-phosphorylation (pERK) assays, when compared to cellstreated with scrambled siRNA (WT) but without alteration in intracellular calcium responses[Ca2+]i as assessed by NFAT-reporter and Fluo-4 calcium assays (SRE maximal response DGKD-KD=5.28 fold change vs. WT=7.20 p=0.0065, pERK maximal response DGKD-KD=24.77, vs. WT=39.46 fold change, p=0.0056). Conversely, DGKD overexpression (DGKD-OE) increased MAPKresponses but suppressed [Ca2+]i responses to alterations in [Ca2+]e (SRE maximal responseDGKD-OE =14.13 fold change vs. WT=9.06 fold change, p=0.01; NFAT maximal response DGKDOE=13.67 fold change vs WT=59.16 fold change, p=0.0001). Our results demonstrate that alterations in DGKD expression cause biased CaSR-signalling. Thisbiased signalling may provide an explanation for the correlation of genotype at the DGKDassociatedlocus with urinary calcium excretion but not serum calcium concentration. Ourfindings suggest that biased CaSR-signalling may be a common cause of nephrolithiasis.  

scholarly journals Hydrochlorothiazide Effectively Reduces Urinary Calcium Excretion in Two Japanese Patients with Gain-of-Function Mutations of the Calcium-Sensing Receptor Gene

2002 ◽  
Vol 87 (7) ◽  
pp. 3068-3073 ◽  
Author(s):  
Kohei Sato ◽  
Yukihiro Hasegawa ◽  
Jun Nakae ◽  
Kenji Nanao ◽  
Ikuko Takahashi ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Japanese Patients ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Gain Of Function ◽  
Dihydroxyvitamin D3 ◽  
Calcium Sensing ◽  
Lower Limit Of Normal

Gain-of-function mutations of the calcium-sensing receptor (CaR) gene cause autosomal dominant and/or sporadic hypocalcemia with hypercalciuria. Because treatment of the hypocalcemia with vitamin D and/or calcium in patients with such mutations results in increased hypercalciuria, nephrocalcinosis, and renal impairment, its use should be limited to alleviating the symptoms of symptomatic patients. Because thiazide diuretics have been successfully used to treat patients with hypercalciuria and hypoparathyroidism, they are theoretically useful in reducing urine calcium excretion and maintaining serum calcium levels in patients with gain-of-function mutations of the CaR gene. In this study, we report on the clinical course, molecular analysis, and effects of hydrochlorothiazide therapy in two Japanese patients with gain-of-function mutations of the CaR gene. Within a few weeks after birth, they developed generalized tonic seizures due to hypocalcemia (serum calcium values: 1.1 mmol/liter and 1.3 mmol/liter, respectively). Despite treatment with the standard dose of 1,25-dihydroxyvitamin D3 in one patient and 1α-hydroxyvitamin D3 in the other, acceptable serum calcium levels near the lower limit of normal were not established, and their urinary calcium excretion inappropriately increased. Addition of hydrochlorothiazide (1 mg/kg) reduced their urinary calcium excretion and maintained their serum calcium concentrations near the lower limit of normal, allowing the 1,25-dihydroxyvitamin D3 and 1α-hydroxyvitamin D3 doses to be reduced, and it alleviated their symptoms. A heterozygous missense mutation was identified in both patients. In one patient, the mutation was A843E in the seventh transmembrane domain of the CaR, and in the other it was L125P in the N-terminal extracellular domain. In vitro transient transfection of their mutant CaR cDNAs into HEK293 cells shifted the concentration-response curve of Ca2+ to the left. In conclusion, two sporadic cases of hypercalciuric hypocalcemia were due to de novo gain-of-function mutations of the CaR gene. Hydrochlorothiazide with vitamin D3 successfully reduced the patients’ urinary calcium excretion and controlled their serum calcium concentrations and symptoms. Thiazide diuretics are effective in patients with gain-of function mutations of the CaR gene.

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