scholarly journals Parathyroid Hormone–Independent Role for the Calcium-Sensing Receptor in the Control of Urinary Calcium Excretion

2012 ◽  
Vol 23 (11) ◽  
pp. 1766-1768 ◽  
Author(s):  
Daniela Riccardi
Keyword(s):  
Parathyroid Hormone ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

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.

USE OF TERIPARATIDE IN A FOUR YEAR OLD PATIENT WITH AUTOSOMAL DOMINANT HYPOCALCAEMIA

2016 ◽  
Vol 101 (9) ◽  
pp. e2.63-e2 ◽  
Author(s):  
Andy Fox ◽  
Rodney Gilbert
Keyword(s):  
Calcium Concentration ◽  
Autosomal Dominant ◽  
Urinary Calcium ◽  
Plasma Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Calcium Supplements ◽  
Calcium Sensing ◽  
Plasma Calcium Concentration

AimWe report the effective use of the synthetic parathyroid hormone (PTH) teriparatide to treat a 4 year old boy with autosomal dominant hypocalcaemia.BackgroundAutosomal Dominant hypocalcaemia is characterised by hypocalcaemia with a lack of parathyroid hormone (PTH) response and inappropriately high urinary calcium excretion. It is caused by gain-of-function mutations in the extracellular calcium sensing receptor which then “over-reads” the extracellular fluid concentration of calcium resulting in suppression of PTH secretion. This then reduces PTH-mediated calcium reabsorption in the distal nephron. Treatment of hypocalcaemia with vitamin D analogues and calcium supplements results in further increases in urinary calcium concentrations, frequently causing nephrocalcinosis and progressive renal damage.Our four year old male patient presented in the neonatal period with seizures secondary to hypocalcaemia and low PTH levels. He suffered repeated seizures with associated tetany. Treatment with alfaclacidol and calcium supplements was able to provide seizure control, however episodes of tetany continued. A heterozygous, activating mutation of the extracellular calcium sensing receptor (c.2528C>A; p.Ala843Glu) was confirmed at age 2. The treatment caused significant hypercalciuria and nephrocalcinosis with a reduction in GFR to 73 ml/mim/m.2 Continuing this therapy would have resulted in end stage kidney disease requiring dialysis/transplantation. The decision was made to try treatment with PTH in order to raise the plasma calcium concentration while minimising the increase in urinary calcium excretion.Funding for treatment was approved by specialised commissioning and treatment was commenced at a dose of 0.4 microg/kg BD.AdministrationTeriparatide is only available in a prefilled pen (Forsteo®) delivering 20 microg in 80 microlitre per dose. Following discussions with the pharmacy team at Great Ormond Street Hospital for Sick Children a protocol was developed to allow these set doses to be diluted prior to administration. By diluting the 20 microg dose to 0.5 ml in a 1 ml syringe a solution containing 40 microg/ml was obtained.OutcomeTreatment was started at 3.66 years of age. Pre-treatment adjusted plasma calcium concentration was 1.96 mmol/L and the urinary calcium excretion was 0.11 mmol/kg/day (normal<0.1). After 5 days of treatment the patient felt very much better and had more energy. The adjusted plasma calcium concentration had risen to 2.09 mmol/L and the urinary calcium excretion had fallen to 0.045 mmol/kg/day.Over the following 9 months the dose of alfacalcidol was reduced from 600 nanograms per day to 300 nanograms per day and calcium supplements were reduced from 16 mmol four times per day to zero. The teriparatide dose was increased from an initial dose of 2 microgram twice daily to 6 microgram twice daily. The plasma calcium has remained above 2 mmol/L apart from a period where further weaning of the alfacalcidol dose was attempted.Rather to our surprise, the patient did not experience symptoms of hypercalcaemia with plasma calcium concentrations within the normal range. His muscle power and tone has increased.We conclude that teriparatide is a useful agent for treating patients with gain-of-function mutations of the calcium-sensing receptor/autosomal dominant hypocalcaemia

scholarly journals Hipocalcemia Crónica por Anticorpos Anti-Recetor do Cálcio

2014 ◽  
Vol 27 (3) ◽  
pp. 399
Author(s):  
Pedro Marques ◽  
Rita Santos ◽  
Branca Cavaco ◽  
Valeriano Leite
Keyword(s):  
Parathyroid Hormone ◽  
Genetic Disorder ◽  
Neck Surgery ◽  
Urinary Calcium ◽  
Clinical Report ◽  
Calcium Sensing Receptor ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Calcium Phosphorus ◽  
Receptor Antibodies

<strong>Introduction:</strong> Hypoparathyroidism is an entity associated with hypocalcemia, more frequently a consequence of neck surgery. An autoimmune etiology is rare and its diagnosis difficult to establish.<br /><strong>Clinical report:</strong> 52 year-old woman, with irrelevant past medical history and no significant familial conditions, referred because of hypocalcemia and basal ganglia calcifications, detected in the course of investigation of myalgias. Besides hypocalcemia (4.6 mg/ dL), hyperphosphatemia (8.7 mg/dL), undetectable parathyroid hormone and low urinary calcium, phosphorus and magnesium were present. Molecular analysis of CaSR gene excluded germinal mutations. Anti-calcium sensing receptor antibodies (anti-CaSR) were present. The patient is asymptomatic and normocalcemic under treatment with calcium and vitamin D.<br /><strong>Discussion:</strong> Although rare, hypocalcemia due to anti-CaSR hypoparathyroidism must be considered in the absence of previous neck surgery, hypocalcemic drugs, familial history or phenotype suggesting a genetic disorder. Low or undetectable parathyroid hormone excludes pseudohypoparathyroidism and anti-CaSR positivity establishes the diagnosis.<br /><strong>Keywords:</strong> Hypocalcemia; Hypoparathyroidism; Autoantibodies; Receptors, Calcium-Sensing.

scholarly journals Recombinant human parathyroid hormone (1–84) is effective in CASR-associated hypoparathyroidism

2020 ◽  
Vol 183 (6) ◽  
pp. K13-K21
Author(s):  
Colin Patrick Hawkes ◽  
Dorothy I Shulman ◽  
Michael A Levine
Keyword(s):  
Parathyroid Hormone ◽  
Traditional Approach ◽  
Calcium Supplementation ◽  
Case Series ◽  
Calcium Sensitivity ◽  
Serum Levels ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Human Parathyroid Hormone

Introduction Gain-of-function mutations in the CASR gene cause Autosomal Dominant Hypocalcemia Type 1 (ADH1), the most common genetic cause of isolated hypoparathyroidism. Subjects have increased calcium sensitivity in the renal tubule, leading to increased urinary calcium excretion, nephrocalcinosis and nephrolithiasis when compared with other causes of hypoparathyroidism. The traditional approach to treatment includes activated vitamin D but this further increases urinary calcium excretion. Methods In this case series, we describe the use of recombinant human parathyroid hormone (rhPTH)1–84 to treat subjects with ADH1, with improved control of serum and urinary calcium levels. Results We describe two children and one adult with ADH1 due to heterozygous CASR mutations who were treated with rhPTH(1–84). Case 1 was a 9.4-year-old female whose 24-h urinary calcium decreased from 7.5 to 3.9 mg/kg at 1 year. Calcitriol and calcium supplementation were discontinued after titration of rhPTH(1–84). Case 2 was a 9.5-year-old male whose 24-h urinary calcium decreased from 11.7 to 1.7 mg/kg at 1 year, and calcitriol was also discontinued. Case 3 was a 24-year-old female whose treatment was switched from multi-dose teriparatide to daily rhPTH(1–84). All three subjects achieved or maintained target serum levels of calcium and normal or improved urinary calcium levels with daily rhPTH(1–84) monotherapy. Conclusions We have described three subjects with ADH1 who were treated effectively with rhPTH(1–84). In all cases, hypercalciuria improved by comparison to treatment with conventional therapy consisting of calcium supplementation and calcitriol.

scholarly journals Effects of calcium-modulating hormones on thiazide receptor density.

1996 ◽  
Vol 7 (7) ◽  
pp. 1052-1057 ◽  
Author(s):  
P Blakely ◽  
D A Vaughn ◽  
D D Fanestil
Keyword(s):  
Parathyroid Hormone ◽  
Calcium Ion ◽  
Excretion Rate ◽  
Urinary Calcium ◽  
Plasma Calcium ◽  
Urinary Calcium Excretion ◽  
Ion Concentration ◽  
Calcium Excretion ◽  
Calcitropic Hormones ◽  
Calcium Ion Concentration

Thiazide diuretic drugs act in the distal convoluted tubule (DCT) to inhibit a Na+Cl- cotransporter and enhance reabsorption of luminal calcium. The density of receptors for thiazides in the rat DCT is known to be increased by adrenocortical steroids, furosemide, and bendroflumethiazide, but decreased by ischemia. Because the DCT is a physiologic site of action by calcitonin and parathyroid hormone, this study examined the effects of these calcitropic hormones in thyroparathyroidectomized Sprague-Dawley rats on (1) the density of the rat thiazide receptor (TZR), as quantitated by binding of (3H)metolazone to renal membranes, and (2) urinary electrolyte excretion rate. Salmon calcitonin (sCT) (20 to 100 ng/h) (1) increased the density of the renal TZR twofold, an effect that is maximal by 6 h after sCT administration, and (2) decreased urinary calcium excretion rate. Adequate dietary calcium must be provided for the effects of sCT to be observed. Regression analysis demonstrated that renal TZR density correlated negatively with total urinary calcium excretion rate but not with plasma calcium ion concentration. In addition, neither rat calcitonin (rCT), at doses that cause hypocalcemia, nor parathyroid hormone, at doses that cause hypercalcemia, produce direct effects on TZR density in the DCT of the thyroparathyroidectomized rat. Our findings indicate that upregulation of TZR by sCT, which occurs independently of plasma calcium-ion concentration, is likely via a calcitonin-like receptor other than that for rat calcitonin itself.

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