Severe hypocalcemia due to a de novo mutation in the fifth transmembrane domain of the calcium-sensing receptor

2005 ◽  
Vol 140A (1) ◽  
pp. 98-101 ◽  
Author(s):  
Stefano Mora ◽  
Ilaria Zamproni ◽  
Maria Carla Proverbio ◽  
Valentina Bozzetti ◽  
Giuseppe Chiumello ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
De Novo ◽  
De Novo Mutation ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

scholarly journals Two novel mutations of the calcium-sensing receptor gene affecting the same amino acid position lead to opposite phenotypes and reveal the importance of p.N802 on receptor activity

2013 ◽  
Vol 168 (2) ◽  
pp. K27-K34 ◽  
Author(s):  
Anne-Sophie Lia-Baldini ◽  
Corinne Magdelaine ◽  
Angélique Nizou ◽  
Coraline Airault ◽  
Jean-Pierre Salles ◽  
...  
Keyword(s):  
Amino Acid ◽  
Transmembrane Domain ◽  
Direct Sequencing ◽  
Receptor Gene ◽  
Amino Acid Position ◽  
Receptor Activity ◽  
Site Directed Mutagenesis ◽  
Missense Mutations ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

ObjectiveGain-of-function mutations of the calcium-sensing receptor (CASR) gene have been identified in patients with sporadic or familial autosomal dominant hypocalcemia (ADH). Inactivating mutations of the CASR gene cause familial hypocalciuric hypercalcemia (FHH). Here, we report two novel CASR mutations affecting the same amino acid (p.N802); one causes ADH and the other atypical FHH.Patients and methodsThe first patient, an 11-year-old girl suffering from hypocalcemia, developed nephrocalcinosis when she was only 5 years old. The second patient is a 30-year-old woman who presented with mild hypercalcemia. PCR amplification of CASR coding exons and direct sequencing of PCR products were used to identify mutations. Site-directed mutagenesis was used to generate mutated CASR cDNAs in an expression plasmid. Using the MAPK assay system and transient transfection of Cos-7 cells with wild-type (WT) and mutated CASR, we studied the responses of these mutated receptors to extracellular Ca2+ and to the negative allosteric CASR modulator, NPS2143.ResultsTwo heterozygous missense mutations (p.N802I and p.N802S) affecting a residue in the sixth transmembrane domain of CASR were identified. In functional tests, the response of the p.N802S mutant to calcium was typical of an inactivating mutation. However, the p.N802I mutant had 70% of the maximally stimulated WT receptor activity even in the absence of extracellular calcium. This constitutive activity was only partially inhibited by the inhibitor, NPS2143.ConclusionsThe asparagine at amino acid position 802 appears to be essential for the activity of the CASR protein and is implicated in the mechanism of CASR signaling.

scholarly journals Homology Modeling of the Transmembrane Domain of the Human Calcium Sensing Receptor and Localization of an Allosteric Binding Site

2003 ◽  
Vol 279 (8) ◽  
pp. 7254-7263 ◽  
Author(s):  
Susanne U. Miedlich ◽  
Lucio Gama ◽  
Klaus Seuwen ◽  
Romain M. Wolf ◽  
Gerda E. Breitwieser
Keyword(s):  
Homology Modeling ◽  
Binding Site ◽  
Transmembrane Domain ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

A novel gain-of-function mutation ( F821L ) in the transmembrane domain of calcium-sensing receptor is a cause of severe sporadic hypoparathyroidism

2004 ◽  
Vol 163 (2) ◽  
pp. 94-98 ◽  
Author(s):  
Masaaki Shiohara ◽  
Tetsuo Mori ◽  
Bai Mei ◽  
Edward M. Brown ◽  
Tomoyuki Watanabe ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Calcium Sensing Receptor ◽  
Gain Of Function ◽  
Calcium Sensing

Improved model building and assessment of the Calcium-sensing receptor transmembrane domain

2008 ◽  
Vol 71 (1) ◽  
pp. 215-226 ◽  
Author(s):  
Lintao Bu ◽  
Mayako Michino ◽  
Romain M. Wolf ◽  
Charles L. Brooks
Keyword(s):  
Model Building ◽  
Transmembrane Domain ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Improved Model

scholarly journals Molecular and clinical analysis of a neonatal severe hyperparathyroidism case caused by a stop mutation in the calcium-sensing receptor extracellular domain representing in effect a human ‘knockout’

2013 ◽  
Vol 169 (1) ◽  
pp. K1-K7 ◽  
Author(s):  
D T Ward ◽  
M Z Mughal ◽  
M Ranieri ◽  
M M Dvorak-Ewell ◽  
G Valenti ◽  
...  
Keyword(s):  
Parathyroid Gland ◽  
Transmembrane Domain ◽  
Stop Codon ◽  
Single Amino Acid ◽  
Total Parathyroidectomy ◽  
Calcium Sensing Receptor ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
Calcium Sensing ◽  
293 Cells

ObjectiveLoss-of-function calcium-sensing receptor (CAR) mutations cause elevated parathyroid hormone (PTH) secretion and hypercalcaemia. Although full Car deletion is possible in mice, most human CAR mutations result from a single amino acid substitution that maintains partial function. However, here, we report a case of neonatal severe hyperparathyroidism (NSHPT) in which the truncated CaR lacks any transmembrane domain (CaRR392X), in effect a full CAR ‘knockout’.Case reportThe infant (daughter of distant cousins) presented with hypercalcaemia (5.5–6 mmol/l corrected calcium (2.15–2.65)) and elevated PTH concentrations (650–950 pmol/l (12–81)) together with skeletal demineralisation. NSHPT was confirmed by CAR gene sequencing (homozygous c.1174C-to-T mutation) requiring total parathyroidectomy during which only two glands were located and removed, resulting in normalisation of her serum PTH/calcium levels.Design and methodsThe R392X stop codon was inserted into human CAR and the resulting mutant (CaRR392X) expressed transiently in HEK-293 cells.ResultsCaRR392X expressed as a 54 kDa dimeric glycoprotein that was undetectable in conditioned medium or in the patient's urine. The membrane localisation observed for wild-type CaR in parathyroid gland and transfected HEK-293 cells was absent from the proband's parathyroid gland and from CaRR392X-transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity.ConclusionsIntriguingly, the patient remained normocalcaemic throughout childhood (2.5 mM corrected calcium, 11 pg/ml PTH (10–71), age 8 years) but exhibited mild asymptomatic hypocalcaemia at age 10 years, now treated with 1-hydroxycholecalciferol and Ca2+ supplementation. Despite representing a virtual CAR knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.

scholarly journals Insights into calcium-sensing receptor trafficking and biased signalling by studies of calcium homeostasis

2018 ◽  
Vol 61 (1) ◽  
pp. R1-R12 ◽  
Author(s):  
Caroline M Gorvin
Keyword(s):  
G Protein ◽  
Calcium Homeostasis ◽  
Calcium Release ◽  
Transmembrane Domain ◽  
Hormone Secretion ◽  
Adaptor Protein ◽  
Structural Motif ◽  
Calcium Excretion ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

The calcium-sensing receptor (CASR) is a class C G-protein-coupled receptor (GPCR) that detects extracellular calcium concentrations, and modulates parathyroid hormone secretion and urinary calcium excretion to maintain calcium homeostasis. The CASR utilises multiple heterotrimeric G-proteins to mediate signalling effects including activation of intracellular calcium release; mitogen-activated protein kinase (MAPK) pathways; membrane ruffling; and inhibition of cAMP production. By studying germline mutations in the CASR and proteins within its signalling pathway that cause hyper- and hypocalcaemic disorders, novel mechanisms governing GPCR signalling and trafficking have been elucidated. This review focusses on two recently described pathways that provide novel insights into CASR signalling and trafficking mechanisms. The first, identified by studying a CASR gain-of-function mutation that causes autosomal dominant hypocalcaemia (ADH), demonstrated a structural motif located between the third transmembrane domain and the second extracellular loop of the CASR that mediates biased signalling by activating a novel β-arrestin-mediated G-protein-independent pathway. The second, in which the mechanism by which adaptor protein-2 σ-subunit (AP2σ) mutations cause familial hypocalciuric hypercalcaemia (FHH) was investigated, demonstrated that AP2σ mutations impair CASR internalisation and reduce multiple CASR-mediated signalling pathways. Furthermore, these studies showed that the CASR can signal from the cell surface using multiple G-protein pathways, whilst sustained signalling is mediated only by the Gq/11 pathway. Thus, studies of FHH- and ADH-associated mutations have revealed novel steps by which CASR mediates signalling and compartmental bias, and these pathways could provide new targets for therapies for patients with calcaemic disorders.

scholarly journals Negative allosteric modulators of the human calcium‐sensing receptor bind to overlapping and distinct sites within the 7‐transmembrane domain

2020 ◽  
Vol 177 (8) ◽  
pp. 1917-1930 ◽  
Author(s):  
Tracy M. Josephs ◽  
Andrew N. Keller ◽  
Elham Khajehali ◽  
Aaron DeBono ◽  
Christopher J. Langmead ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Allosteric Modulators ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Cinacalcet therapy in an infant with an R185Q calcium-sensing receptor mutation causing hyperparathyroidism: a case report and review of the literature

2019 ◽  
Vol 32 (3) ◽  
pp. 305-310 ◽  
Author(s):  
Thomas E. Forman ◽  
Anna-Kaisa Niemi ◽  
Priya Prahalad ◽  
Run Zhang Shi ◽  
Laura M. Nally
Keyword(s):  
Side Effects ◽  
Pediatric Patients ◽  
De Novo ◽  
Clinical Course ◽  
Review Of The Literature ◽  
Calcium Sensing Receptor ◽  
Case Presentation ◽  
Calcium Sensing ◽  
Calcium Phosphorus ◽  
Pharmacologic Agents

Abstract Background Neonatal severe hyperparathyroidism (NSHPT) is commonly treated with either parathyroidectomy or pharmacologic agents with varying efficacy and numerous side effects. Reports of using cinacalcet for NSHPT have increased, however, the effective dose for pediatric patients from the onset of symptoms through infancy has not been established. Case presentation We describe the clinical course of a newborn with a de novo R185Q mutation in the calcium-sensing receptor (CASR) gene, causing NSHPT. The infant received cinacalcet from the first days of life until 1 year of age. Conclusions Cinacalcet therapy effectively controlled the patient’s serum calcium, phosphorus, and parathyroid hormone (PTH) levels without side effects.

scholarly journals Familial hypocalciuric hypercalcemia with a de novo heterozygous mutation of calcium-sensing receptor

2015 ◽  
Vol 2015 ◽  
Author(s):  
Katsumi Taki ◽  
Takahiko Kogai ◽  
Junko Sakumoto ◽  
Takashi Namatame ◽  
Akira Hishinuma
Keyword(s):  
Bone Disease ◽  
De Novo ◽  
Perinatal Period ◽  
Pedigree Analysis ◽  
Normal Serum ◽  
Bone Diseases ◽  
Heterozygous Mutation ◽  
List Type ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Summary A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year-old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes. Learning points The phenotype and severity of CASR mutations are thought to be dependent on genotypes. We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases. Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation.

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