Calcium-sensing Receptor Gene Research Articles

Inherited conditions resulting in nephrolithiasis.

Prevalence of pediatric urolithiasis is increasing, which is definitively visible in increasing numbers of presentations in emergency or outpatient clinics. In pediatric patients, a genetic or metabolic disease has to be excluded, so that adequate treatment can be installed as early as possible. Only then either recurrent stone events and chronic or even end-stage kidney disease can be prevented. The genetic background of mostly monogenic kidney stone diseases was unravelled recently. In hypercalcuria, for example, the commonly used definition of idiopathic hypercalciuria was adopted to the genetic background, here three autosomal recessive hereditary forms of CYP24A1, SLC34A1 and SLC34A3 associated nephrocalcinosis/urolithiasis with elevated 1.25-dihydroxy-vitamin D3 (1.25-dihydroxy-vitamin D3) (calcitriol) levels. In addition either activating or inactivating mutations of the calcium-sensing receptor gene lead either to hypocalcemic hypercalciuria or hypercalcemic hypocalciuria. In primary hyperoxaluria, a third gene defect was unravelled explaining most of the so far unclassified patients. In addition, these findings lead to new treatment options, which are currently evaluated in phase III studies. Kidney stones are not the disease itself, but only its first symptom. The underlying disease has to be diagnosed in every pediatric patient with the first stone event.

Identification of Key Biomarkers and Potential Molecular Mechanisms in Oral Squamous Cell Carcinoma by Bioinformatics Analysis.

The aim of this study was to explore the key genes, microRNA (miRNA), and the pathogenesis of oral squamous cell carcinoma (OSCC) at the molecular level through the analysis of bioinformatics, which could provide a theoretical basis for the screening of drug targets. Data of OSCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified via GEO2R analysis. Next, protein-protein interaction (PPI) network of DEGs was constructed through Search Tool for the Retrieval of Interacting Gene and visualized via Cytoscape, whereas the hub genes were screened out with Cytoscape. Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Database for Annotation, Visualization and Integrated Discovery. The miRNA, which might regulate hub genes, were screened out with TargetScan and GO and KEGG analysis of miRNA was performed by DNA Intelligent Analysis-miRPath. Survival analyses of DEGs were conducted via the Kaplan-Meier plotter. Finally, the relationships between gene products and tumors were analyzed by Comparative Toxicogenomics Database. A total of 121 differential genes were identified. One hundred thirty-five GO terms and 56 pathways were obtained, which were mainly related to PI3K-Akt signals pathway, FoxO signaling pathway, Wnt signaling pathway, cell cycle, p53 signaling pathway, cellular senescence, and other pathways; 10 genes were identified as hub genes through modules analyses in the PPI network. Finally, a survival analysis of 10 hub genes was conducted, which showed that the low expression of matrix metalloproteinase (MMP)1, MMP3, and C-X-C motif chemokine ligand (CXCL)1 and the high expression of CXCL9 and CXCL10 resulted in a significantly poor 5-year overall survival rate in patients with OSCC. In this study, the DEGs of OSCC was analyzed, which assists us in a systematic understanding of the pathogenicity underlying occurrence and development of OSCC. The MMP1, MMP3, CXCL1, CXCL9, and CXCL10 genes might be used as potential targets to improve diagnosis and as immunotherapy biomarkers for OSCC.

Association between calcium-sensing receptor (CaSR) R990G, CaSR A986S, and CaSR Q1011E gene polymorphisms and the risk of urolithiasis: a meta-analysis

BackgroundsIn the last two decades, studies have been widely carried out to assess the association between single-nucleotide polymorphisms (SNPs) of calcium-sensing receptor (CaSR) gene in exon 7 and the risk of urolithiasis. However, inconsistency across the studies was reported. Therefore, our current study aimed to perform a meta-analysis concerning the association between the risk of urolithiasis and the gene polymorphisms of CaSR R990G, CaSR A986S, and CaSR Q1011E.MethodsPublished papers from PubMed, Embase, Cohcrane, and Web of science were included for the study, and they were analyzed using fixed or random effect model.ResultsA total of 11 papers consisting of eight papers evaluating CaSR R990G, nine papers evaluating CaSR A986S, and five papers evaluating CaSR Q1011E were included in our analysis. Our pooled calculation found that protective effect against urolithiasis was observed in R allele and RR genotype of CaSR R990G and A allele and AA genotype of CaSR A986S. Conversely, increased susceptibility to urolithiasis was found in G allele and RG genotype of CaSR R990G and S allele of CaSR A986S. Interestingly, our findings in sub-group analysis confirmed that the correlation between CaSR R990G and urolithiasis was found in Caucasian population. Meanwhile, in Asian population, the association was observed in CaSR A986S.ConclusionsCaSR R990G and CaSR A986S, but not CaSR Q1011E, are associated with the risk of urolithiasis.

Heterozygous Mutation (Q459R) in the Calcium-Sensing Receptor Gene Causes Familial Hypocalciuric Hypercalcemia 1 (FHH1).

Several heterozygous loss-of-function mutations in the calcium-sensing receptor gene (CASR) leading to elevated ionized serum calcium and familial hypocalciuric hypercalcemia 1 (FHH1) have been characterized. Few mutations are not pathogenic, and previous studies suggested that the Q459R mutation does not result in an FHH1 phenotype. We identified a family with a heterozygous CASR Q459R mutation and characterized their calcium homeostasis and the pathophysiological mechanisms of a homozygous and heterozygous Q459R mutation in vitro. The index patient and her family had clinical, biochemical, and genetic analyses performed. In vitro functional characterization of homozygous and heterozygous (Q459R) mutations was conducted by determining CaSR cell-surface expression and inositol monophosphate (IP1) signaling in transiently transfected human embryonic kidney 293A (HEK293A) cells. All 3 heterozygous carriers had mild asymptomatic hypercalcemia, hypocalciuria, and 2 had elevated serum parathyroid hormone (PTH). In vitro characterization in HEK293A cells revealed that CASR Q459R is a loss-of-function mutation with no impact on cell-surface expression. Cells with the homozygous Q459R genotype had significantly reduced calcium potency of IP1 signaling compared to wild type, whereas the heterozygous Q459R also had lower calcium potency albeit not significantly different from wild type. A loss-of-function Q459R mutation in CASR in a family caused FHH1 characterized by elevated ionized calcium and PTH and low calcium excretion. The marked presence of CaSR at the membrane and inhibition of IP1 signaling in vitro suggest that calcimimetics may be functional in patients with this mutation, which seems to be a mild loss-of-function mutation associated with autosomal dominant transmission of FHH1.

Calcium-sensing receptor deletion in the mouse esophagus alters barrier function.

Calcium-sensing receptor (CaSR) is the molecular sensor by which cells respond to small changes in extracellular Ca2+ concentrations. CaSR has been reported to play a role in glandular and fluid secretion in the gastrointestinal tract and to regulate differentiation and proliferation of skin keratinocytes. CaSR is present in the esophageal epithelium, but its role in this tissue has not been defined. We deleted CaSR in the mouse esophagus by generating keratin 5 CreER;CaSRFlox+/+compound mutants, in which loxP sites flank exon 7 of CaSR gene. Recombination was initiated with multiple tamoxifen injections, and we demonstrated exon 7 deletion by PCR analysis of genomic DNA. Quantitative real-time PCR and Western blot analyses showed a significant reduction in CaSR mRNA and protein expression in the knockout mice (EsoCaSR-/-) as compared with control mice. Microscopic examination of EsoCaSR-/- esophageal tissues showed morphological changes including elongation of the rete pegs, abnormal keratinization and stratification, and bacterial buildup on the luminal epithelial surface. Western analysis revealed a significant reduction in levels of adherens junction proteins E-cadherin and β catenin and tight junction protein claudin-1, 4, and 5. Levels of small GTPase proteins Rac/Cdc42, involved in actin remodeling, were also reduced. Ussing chamber experiments showed a significantly lower transepithelial resistance in knockout (KO) tissues. In addition, luminal-to-serosal-fluorescein dextran (4 kDa) flux was higher in KO tissues. Our data indicate that CaSR plays a role in regulating keratinization and cell-cell junctional complexes and is therefore important for the maintenance of the barrier function of the esophagus.NEW & NOTEWORTHY The esophageal stratified squamous epithelium maintains its integrity by continuous proliferation and differentiation of the basal cells. Here, we demonstrate that deletion of the calcium-sensing receptor, a G protein-coupled receptor, from the basal cells disrupts the structure and barrier properties of the epithelium.

Expanding the spectrum of genetic variants in the calcium-sensing receptor (CASR) gene in hypercalcemic individuals.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominantly inherited disorder with overlapping biochemistry profile with primary hyperparathyroidism (PHPT), making the correct diagnosis a challenge. The objective of the study was to evaluate the results of the clinical work-up of a large group of hypercalcemic individuals. Cross-sectional study. Patients undergoing clinical work-up of hypercalcemia. Molecular genetic analysis of the CASR gene and exon 2 of the AP2S1 gene. Plasma levels of ionized calcium and PTH as well as calcium creatinine clearance ratio (CCCR). A rare CASR variant was identified in 38 of 624 index patients (6.1%). A total of 18 CASR variants identified in this study were novel. No variants were identified in exon 2 of the AP2S1 gene. The majority of the variants (N=16) were classified as likely pathogenic. The level of plasma calcium, plasma PTH and the CCCR was not affected by the type of variant (ie nonsense vs missense) (all P-values >.05). The CCCR was found to be significantly lower for variants in the transmembrane domain compared with variants located in the extracellular domain (P<.05). Plasma levels of calcium and PTH were not associated with the location of the variant (P>.05). We expanded the spectrum of CASR variants in hypercalcemia with 18 novel variants, and suggest that the location of the CASR variant may affect calcium excretion as determined by the CCCR.

MON-193 RENAL TRANSPLANTATION IN A PATIENT WITH FAMILIAL SYNDROME OF HYPOCALCEMIA WITH HYPERCALCIURIA

The calcium sensing receptor regulates the secretion of parathyroid hormone in response to changes in the extracellular calcium concentration and mutations that result in gain of function of this receptor are associated with with familial hypocalcemia with hypercalciuria. The high urinary calcium excretion leads to nephrocalcinosis and renal insufficiency. We present a case of a patient with end stage kidney disease due to nephrocalcinosis from familial hypocalcemia with hypercalciuria, who subsequently underwent renal transplantation with complete resolution of hypercalciuria. This is the first reported case of renal transplantation in a patient with familial hypocalcemic hypercalciuria. Case report: 58 year old female developed end stage kidney disease due to nephrocalcinosis. Nephrocalcinosis was secondary to familial hypoparathyroidism and she had known mutations in calcium sensing receptors and hence chronic hypocalcemia (1.8-1.9mmol/l) and hypercalciuria( 3.2mmol/l) . She subsequently underwent non directed living donor transplantation. Within 1 week after renal transplantation the urinary calcium concentration was measured and this was completely within normal limits with urine calcium concentration of 1 mmol/l and calcium/creatinine ratio of 0.29 ( normal range 0.06- 0.45mole ratio). Subsequent urine calcium concentrations are less than 0.20mmol/l and her graft function remains excellent. Discussion: This is the first case report of successful renal transplantation in a case of familial hypoparathyroidism with known gain of function or activating mutation of calcium sensing receptor which results in hypocalcemia and hypercalciuria. The calcium sensing receptor gene is expressed in the parathyroid glands and kidneys . This receptor regulates the the secretion of parathyroid hormone and reabsorption of calcium by the renal tubules in response to alterations of serum calcium levels. Gain of function mutation of the calcium sensing receptor gene will suppress the parathyroid hormone and increase the excretion of urinary calcium at inappropriately low serum calcium levels. The high urinary calcium concentration drives polyuria and dehydration and hence subsequently leads to nephrocalcinosis and renal insufficiency. With renal transplantation, we are essential replacing the affected abnormal calcium sensing receptors with normal calcium sensing receptor and hence normalising urinary calcium, thereby eliminating the risk of nephrocalcinosis in the graft. Conclusions: Renal transplantation is a safe and effective way of treating end stage kidney disease in patients with nephrocalcinosis due to familial hypocalcemia and hypercalciuria.

Abstract 133: The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments

Abstract Cancer-induced hypercalcemia (CIH) is common in cancer patients with metastatic disease and in up to 30% of cases without metastasis. During malignancy, tumor cells secrete factors such as parathyroid hormone related protein (PTHrP) that causes the destruction of bone tissue, or osteolysis. The resulting persistent osteolysis leads to a progressive increase in systemic calcium or CIH. High circulating Ca2+ is sensed by the calcium-sensing receptor (CaSR), which plays a significant role in maintaining Ca2+ homeostasis, and also stimulates the secretion of PTHrP which promotes tumor cell proliferation and motility. Moreover, more than 200 mutations including single nucleotide polymorphisms (SNPs) in the CaSR gene have been described, including the inactivating A986S CaSR at rs1801725 and Q1011E CaSR at rs1801726 SNPs with reduced sensitivity to Ca2+ . Although the CaSR is the major cell surface Ca2+ sensor in most cell types, its function in the Ca2+ rich bone microenvironment remains unclear. We show that high Ca2+ adaptation of MDA-MB-231 cells, did not lead to altered expression of the receptor in the surviving cells. However, the receptor was desensitized to high Ca2+ and the cells were more motile and formed larger colonies in 3D cultures. Meanwhile, gene expression profiling of triple negative breast cancer cells (TNBC) cells transiently exposed to high Ca2+ reveals the expression of early response genes and Ca2+ -inducible genes with known functions in tumor growth and/or motility. Since breast cancer (BC) frequently metastasizes to skeletal tissues, these data suggest that BC cells that successfully colonize the bone microenvironment undergo high Ca2+ adaptation or priming via the expression of high Ca2+ inducible genes that facilitate cell growth and/or motility. Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Sarrah E. Widatalla, Diva S. Whalen, Stephen D. Williams, Olga Y. Korolkova, Amos M. Sakwe. The role of the calcium-sensing receptor (CaSR) in the adaptation of breast cancer cells in high Ca2+ microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 133.

A Novel Mutation in Calcium-Sensing Receptor Presenting as Familial Hypocalciuric Hypercalcemia in a Young Man

Familial hypocalciuric hypercalcemia (FHH) is considered a relatively benign condition characterized by elevated serum calcium with relatively low urinary calcium excretion. It typically results from an altered set point in calcium homeostasis originating from mutations in the calcium-sensing receptor (CASR), AP2S1, or GNA11 genes, which encode for the calcium-sensing receptor (CaSR), adaptor-related protein complex 2, and G-protein alpha-11 subunit, respectively. Despite numerous reports of novel variants in these genes associated with FHH, new variants continue to be discovered. We describe a 20-year-old man with a family history of hypercalcemia who had clinical findings compatible with FHH and no evidence of multiple endocrine neoplasia who underwent CASR gene sequencing for evaluation of hypercalcemia. Parathyroid gland single-photon emission computerized tomography scan was normal. CASR gene sequencing revealed a previously unreported heterozygous intronic variant at position 1608+3A>G (chromosome 3: 121994892) resulting in a 77-residue deletion. His mother has a history of bipolar disorder and hyperparathyroidism with an adenoma found on imaging, yet our patient had no evidence of adenoma and therefore no surgical intervention was recommended. Given that CaSR plays a role in parathyroid growth, some variants in CASR may ultimately lead to parathyroid hypertrophy and be mistaken for primary hyperparathyroidism. Long-term clinical follow up will be helpful in understanding the ultimate effects of specific CASR mutations on parathyroid growth or progression to significant hypercalcemia.

Identification of Key Biomarkers and Potential Molecular Mechanisms in Renal Cell Carcinoma by Bioinformatics Analysis.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, caused by renal epithelial cells. RCC remains to be a challenging public health problem worldwide. Metastases that are resistant to radiotherapy and chemotherapy are the major cause of death from cancer. However, the underlying molecular mechanism regulating the metastasis of RCC is poorly known. Publicly available databases of RCC were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using GEO2R analysis, whereas the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by Gene Set Enrichment Analysis (GSEA) and Metascape. Protein-protein interaction (PPI) network of DEGs was analyzed by STRING online database, and Cytoscape software was used for visualizing PPI network. Survival analysis of hub genes was conducted using GEPIA online database. The expression levels of hub genes were investigated from The Human Protein Atlas online database and GEPIA online database. Finally, the comparative toxicogenomics database (CTD; http://ctdbase.org) was used to identify hub genes associated with tumor or metastasis. We identified 229 DEGs comprising 135 downregulated genes and 94 upregulated genes. Functional analysis revealed that these DEGs were associates with cell recognition, regulation of immune, negative regulation of adaptive immune response, and other functions. And these DEGs mainly related to P53 signaling pathway, cytokine-cytokine receptor interaction, Natural killer cell mediated cytotoxicity, and other pathways are involved. Ten genes were identified as hub genes through module analyses in the PPI network. Finally, survival analysis of 10 hub genes was conducted, which showed that the MMP2 (matrix metallo peptidase 2), DCN, COL4A1, CASR (calcium sensing receptor), GPR4 (G protein-coupled receptor 4), UTS2 (urotensin 2), and LDLR (low density lipoprotein receptor) genes were significant for survival. In this study, the DEGs between RCC and metastatic RCC were analyzed, which assist us in systematically understanding the pathogeny underlying metastasis of RCC. The MMP2, DCN, COL4A1, CASR, GPR4, UTS2, and LDLR genes might be used as potential targets to improve diagnosis and immunotherapy biomarkers for RCC.

Identification of a novel calcium-sensing receptor (CASR) gene mutation in a patient with familial hypocalciuric hypercalcemia

Identification of a novel calcium-sensing receptor (CASR) gene mutation in a patient with familial hypocalciuric hypercalcemia

Two novel mutations in the Calcium Sensing Receptor (CASR) gene in patient s with biochemical investigations suggestive of Familial Hypocalciuric Hypercalcemia (FHH)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MEN1-Related Hyperparathyroidism: Response to Cinacalcet and Calcium-Sensing Receptor Gene Variant Arg990Gly

MEN1-Related Hyperparathyroidism: Response to Cinacalcet and Calcium-Sensing Receptor Gene Variant Arg990Gly

Genetic variants of calcium sensing receptor gene and risk of colorectal cancer: A case-control study.

Objectives:To determine the role of two genetic variants, (rs3804594) and (rs1801725), in calcium sensing receptor (CASR) gene with colorectal cancer (CRC) risk in patients visited King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia.Methods:Genomic DNA was extracted, by commercial DNA extraction kit, from whole blood of 100 CRC patients and 124 controls who visited KAUH from January 2016 to September 2016. Then genotype and allele distributions of both variants were determined by PCR-RFLP and DNA sequencing techniques. All statistical analyses were performed by unpaired t-test and P-values <0.05 were considered statistically significant.Results:Data obtained from χ2 test showed that intron 4 variant in CASR gene was distributed 100% normally in the 224 participants, however, exon 7 variant showed 100% homozygous distribution in the controls; whereas, in CRC patients it was distributed equally into 50% heterozygous and 50% homozygous with no detection for wild type.Conclusion:Intron 4 variant (rs3804594) in CASR gene is not correlated to CRC risk. However, more investigations are needed to elucidate the role of CASR gene exon 7 (rs1801725) variant in CRC development as the current results are not definitive.

Calcium-Sensing Receptor Arbitrates Hypoxia-Induced Proliferation of Pulmonary Artery Smooth Muscle Cells via the G Protein-PLC-IP3 Pathway.

Pulmonary arterial hypertension (PAH), also known as broilers ascites syndrome, is characterized by hypoxia, pulmonary artery pressure, and right heart failure. However, less information is available about the molecular mechanisms of PAH. We evaluated the mediation of calcium-sensing receptor by inducing hypoxia for the possible proliferation of pulmonary artery smooth muscle cells via the G protein pathway. For this purpose, we used an in vitro trial of chicken cell culture and confirmed our results by using immunohistochemistry, immunofluorescence staining, quantitative real-time polymerase chain reaction assay, and Western blotting analysis. Our results showed that the mRNA and protein expression levels of calcium-sensing receptor (CaSR) were significantly upregulated in cells when co-incubated with CaCl2. However, the levels of mRNA and protein were obviously decreased when supplemented with blocking agents (NiCl2, 2-APB, and D609). Furthermore, the experimentally induced hypoxia also upregulated the expression of CaSR gene as compared to CaSR gene expression in control cells. Together, these results indicate that hypoxia plays an important role in the expression of CaSR gene in pulmonary artery smooth muscle cells and reveals new targets for the CaSR excited hypothesis to prevent and control PAH in chickens.

Calcium-sensing receptor: evidence and hypothesis for its role in nephrolithiasis.

Calcium-sensing receptor (CaSR) is a plasma-membrane G protein-coupled receptor activated by extracellular calcium and expressed in kidney tubular cells. It inhibits calcium reabsorption in the ascending limb and distal convoluted tubule when stimulated by the increase of serum calcium levels; therefore, these tubular segments are enabled by CaSR to play a substantial role in the regulation of serum calcium levels. In addition, CaSR increases water and proton excretion in the collecting duct and promotes phosphate reabsorption and citrate excretion in the proximal tubule. These CaSR activities form a network in which they are integrated to protect the kidney against the negative effects of high calcium concentrations and calcium precipitates in urine. Therefore, the CaSR gene has been considered as a candidate to explain calcium nephrolithiasis. Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5'-untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion. These findings suggest that CaSR may play a complex role in lithogenesis through different pathways having different relevance under different clinical conditions.

Genetic polymorphism (rs6776158) in CaSR gene is associated with risk of nephrolithiasis in Chinese population.

The objective of this study is to find about the association between calcium-sensing receptor (CaSR) genetic variants and susceptibility to nephrolithiasis in the Chinese Han population.This hospital-based case-control study included 319 nephrolithiasis cases and 378 healthy controls subjects. Two SNPs in CaSR were genotyped using the TaqMan assay.We found that subjects carrying the G allele of rs6776158 (AG and GG) had significantly higher risk of nephrolithiasis compared to the AA genotype (P = .015 and .009, respectively).Our results indicate that rs6776158 polymorphism that might elevate the risk of nephrolithiasis in the Chinese population.

One pedigree analysis of a familial hypocalciuric hypercalcemia caused by a new heterozygous mutation in calcium-sensing receptor gene

Medical history and physical examinations were performed to assess the clinical manifestations and growth of one patient with familial hypocalciuric hypercalcemia(FHH). Clinical data, including histories of his parents and 3 maternal relatives were collected. Serum parathyroid hormone(PTH), calcium, phosphorus, 24-hour urinary calcium, and 24-hour urinary calcium to creatinine ratio(UCCR)were measured or calculated. Meanwhile, after peripheral blood samples were collected and genomic DNA was extracted, the whole exome sequencing to detect gene mutations of the proband was performed. Further family screenings were also performed by Sanger sequencing to assess the relationship between genotype and phenotype. The results showed that the proband with motor developmental delays had severe hypercalcemia(4.20 mmol/L), while his mother without clinical symptoms had a higher blood calcium within the normal range(2.57 mmol/L). However, their urinary calcium levels were both low(UCCR< 0.01). The C→T heterozygous missense mutation was found by exome sequencing at nucleotide 1243 within exon 4 of calcium sensing receptor(CaSR)gene in the proband, which caused a substitution of Arginine to Tryptophan(R415W). Sanger sequencing confirmed the same mutation in his mother. There was no mutation in other family members. (Chin J Endocrinol Metab, 2018, 34: 583-586) Key words: Hypercalcemia; Calcium-sensing receptor; Familial hypocalciuric hypercalcemia

Gain-of-Function R990G Polymorphism of the Calcium-Sensing Receptor Gene: Gender-Related Effects in Patients with Coronary Heart Disease

Background: Activating the calcium-sensing receptor (CaSR), which regulates extracellular calcium, has been suggested to possibly decrease renin expression, thus playing a role in regulating the blood pressure via the renin-angiotensin-aldosterone system. Objectives: Considering this hypothesis, the aim of this study was to find the relationship between the gain-of-function variation of the CaSR gene, R990G (A 0.05). Conclusions: The common AA genotype of CaSR R990G was found to be related to hypertension in CHD patients while showing a higher association with hypertension, especially in women. We also suggest that the CaSR R990G AA genotype may have diverse effects on serum lipids and that the genetic effect could differ by gender.

De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism

Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient.