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 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.

scholarly journals Identification and Functional Characterization of a Novel Mutation in the Calcium-Sensing Receptor Gene in Familial Hypocalciuric Hypercalcemia: Modulation of Clinical Severity by Vitamin D Status

2007 ◽  
Vol 92 (7) ◽  
pp. 2616-2623 ◽  
Author(s):  
Katerina Zajickova ◽  
Jana Vrbikova ◽  
Lucie Canaff ◽  
Peter D. Pawelek ◽  
David Goltzman ◽  
...  
Keyword(s):  
Vitamin D ◽  
Gene Mutation ◽  
Clinical Severity ◽  
Vitamin D Status ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Casr Gene ◽  
Calcium Sensing ◽  
Serum Pth

Abstract Context: Familial hypocalciuric hypercalcemia (FHH) is a benign condition associated with heterogeneous inactivating mutations in the calcium-sensing receptor (CASR) gene. Objective: The objective of the study was to identify and characterize a CASR mutation in a moderately hypercalcemic, hyperparathyroid individual and his family and assess the influence of vitamin D status on the clinical expression of the defect. Subjects: We studied a kindred with FHH, in which the proband (a 34-yr-old male) was initially diagnosed with primary hyperparathyroidism due to frankly elevated serum PTH levels. Methods: CASR gene mutation analysis was performed on genomic DNA of the proband and family members. The mutant CASR was functionally characterized by transient transfection studies in kidney cells in vitro. Results: A novel heterozygous mutation (F180C, TTC>TGC) in exon 4 of the CASR gene was identified. Although the mutant receptor was expressed normally at the cell surface, it was unresponsive with respect to intracellular signaling (MAPK activation) to increases in extracellular calcium concentrations. The baby daughter of the proband presented with neonatal hyperparathyroidism with markedly elevated PTH. Vitamin D supplementation of both the proband and the baby resulted in reduction of serum PTH levels to the normal range. The serum calcium level remained at a constant and moderately elevated level. Conclusion: The identification of a novel CASR gene mutation established the basis of the hypercalcemia in the kindred. Concomitant vitamin D deficiency modulates the severity of the presentation of FHH.

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 SAT-404 Neonatal Hypocalcemic Seizures in Offspring of a Mother with Familial Hypocalciuric Hypercalcemia Type 1 (FHH1)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Fadil M Hannan ◽  
Poonam Dharmaraj ◽  
Caroline M Gorvin ◽  
Astha Soni ◽  
Nick D Nelhans ◽  
...  
Keyword(s):  
Serum Calcium ◽  
Mutational Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Hek293 Cells ◽  
Familial Hypocalciuric Hypercalcemia ◽  
Loss Of Function ◽  
Calcium Sensing Receptor ◽  
Benign Condition ◽  
Calcium Sensing

Abstract Background: Familial hypocalciuric hypercalcemia type 1 (FHH1) is caused by loss-of-function mutations of the calcium-sensing receptor (CaSR), and considered to be a benign condition associated with mild-to-moderate hypercalcemia (1). However, the children of parents with FHH1 can develop a variety of disorders of calcium homeostasis in infancy. Objective: To further characterise the range of calcitropic phenotypes in the children of a mother with FHH1. Methods: We assessed a three generation FHH kindred by clinical, biochemical and mutational analysis following informed consent. Results: The kindred comprised a hypercalcemic male, his daughter who had hypercalcemia and hypocalciuria, and her four children, of whom two had asymptomatic hypercalcemia, one was normocalcemic, and one suffered from transient hypocalcemic seizures during infancy. The hypocalcemic infant had a serum calcium of 1.57 mmol/L (normal, 2.0-2.8) and PTH of 2.2 pmol/L (normal, 1.0-9.3) as a consequence of maternal hypercalcemia, and required treatment with I-V calcium gluconate infusions. Mutational analysis identified a novel heterozygous p.Ser448Pro CaSR variant in the hypercalcemic family members, but not in the children with hypocalcemia or normocalcemia. Three-dimensional modelling using a reported crystal structure of the dimeric CaSR showed the mutated Ser448 residue to be located in the CaSR extracellular domain, and predicted the p.Ser448Pro variant to disrupt a hydrogen bond interaction across the extracellular CaSR dimer interface. The variant Pro448 CaSR, when expressed in HEK293 cells, was shown to significantly impair CaSR-mediated intracellular calcium mobilisation and mitogen-activated protein kinase (MAPK) responses following stimulation with extracellular calcium, thereby demonstrating it to represent a loss-of-function mutation. Conclusion: These studies have identified a novel loss-of-function CaSR mutation which caused asymptomatic hypercalcemia in a mother and her children who had inherited the mutation. However, one child who did not inherit the mutation developed transient neonatal hypocalcemic seizures as a consequence of maternal hypercalcemia. These findings highlight the importance of assessing serum calcium and undertaking CaSR mutational analysis in the newborn offspring of a mother with FHH1. Reference: (1) Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018; 15(1): 33-51.

scholarly journals Calcium-Sensing Receptor and Regulation of WNK Kinases in the Kidney

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1644
Author(s):  
Daria S. Ostroverkhova ◽  
Junda Hu ◽  
Vadim V. Tarasov ◽  
Tatiana I. Melnikova ◽  
Yuri B. Porozov ◽  
...  
Keyword(s):  
Urinary Calcium ◽  
Calcium Handling ◽  
Transport Systems ◽  
Calcium Excretion ◽  
Loss Of Function ◽  
Distal Nephron ◽  
Calcium Sensing Receptor ◽  
Gain Of Function ◽  
Casr Gene ◽  
Calcium Sensing

The kidney is essential for systemic calcium homeostasis. Urinary calcium excretion can be viewed as an integrative renal response to endocrine and local stimuli. The extracellular calcium-sensing receptor (CaSR) elicits a number of adaptive reactions to increased plasma Ca2+ levels including the control of parathyroid hormone release and regulation of the renal calcium handling. Calcium reabsorption in the distal nephron of the kidney is functionally coupled to sodium transport. Apart from Ca2+ transport systems, CaSR signaling affects relevant distal Na+-(K+)-2Cl− cotransporters, NKCC2 and NCC. NKCC2 and NCC are activated by a kinase cascade comprising with-no-lysine [K] kinases (WNKs) and two homologous Ste20-related kinases, SPAK and OSR1. Gain-of-function mutations within the WNK-SPAK/OSR1-NKCC2/NCC pathway lead to renal salt retention and hypertension, whereas loss-of-function mutations have been associated with salt-losing tubulopathies such as Bartter or Gitelman syndromes. A Bartter-like syndrome has been also described in patients carrying gain-of-function mutations in the CaSR gene. Recent work suggested that CaSR signals via the WNK-SPAK/OSR1 cascade to modulate salt reabsorption along the distal nephron. The review presented here summarizes the latest progress in understanding of functional interactions between CaSR and WNKs and their potential impact on the renal salt handling and blood pressure.

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.  

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

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