Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism

Hannan, Fadil; Thakker, Rajesh V.

doi:10.1016/j.beem.2013.04.007

Cited by 123 publications

(152 citation statements)

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“…2-4), as more commonly reported for mutations in human kindreds with familial hypocalciuric hypercalcemia (FHH) or neonatal severe primary hyperparathyroidism (NSHPT) (reviews: [36][37][38]). The finding that E max was reduced is consistent with the idea that Ca 2+ o binding and Ca 2+ o -dependent changes in receptor conformation were normal in the extracellular VFT and Cys-rich domains, but that coupling of the activated receptor to its signalling apparatus in the dimeric heptahelical domains was defective as a result of impaired binding of partner proteins including G-proteins and enzymes.…”

Section: Discussionmentioning

confidence: 99%

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

et al. 2014

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Edited by Ned ManteiKeywords: Calcium-sensing receptor G-protein coupled receptor Biased signalling Phosphatidylinositol-specific phospholipase-C Adenosine 3 0 ,5 0 -cyclic monophosphate ERK 1/2 a b s t r a c tThe calcium-sensing receptor (CaSR) couples to signalling pathways via intracellular loops 2 and 3, and the C-terminus. However, the requirements for signalling are largely undefined. We investigated the impacts of selected point mutations in iL-2 (F706A) and iL-3 (L797A and E803A), and a truncation of the C-terminus (R866X) on extracellular Ca 2+ (Ca 2+ o )-stimulated phosphatidylinositolspecific phospholipase-C (PI-PLC) and various other signalling responses. CaSR-mediated activation of PI-PLC was markedly attenuated in all four mutants and similar suppressions were observed for Ca 2+ o -stimulated ERK 1/2 phosphorylation. Ca 2+ o -stimulated intracellular Ca 2+ (Ca 2+ i ) mobilization, however, was relatively preserved for the iL-2 and iL-3 mutants and suppression of adenylyl cyclase was unaffected by either E803A or R866X. The CaSR selects for specific signalling pathways via the proximal C-terminus and key residues in iL-2, iL-3.

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Section: Discussionmentioning

confidence: 99%

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

et al. 2014

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“…It is characterized in most cases by a dysregulation of the phosphor-calcic metabolism caused by an inactivating mutation of the gene that encodes the CASR [120]. The condition is characterized by lifelong mild hypercalcaemia associated with inappropriately unaccommodated levels of PTH and a urinary calcium excretion that is inappropriately low in the presence of the corresponding hypercalcaemia.…”

Section: Fhhmentioning

confidence: 97%

“…FHH type 1 (OMIM # 145980) is responsible for 65 % of cases and is due to inactivating mutations in the CASR gene localized on chromosome 3: 3q21.1. The CASR gene encodes the calcium-sensing receptor the loss of whose function results in a reduction in the sensitivity of parathyroid and renal cells to the serum calcium concentration, and hypercalcaemia is perceived as normal [120]. The remaining 35 % of FHH patients have mutations on chromosome 19: either mutation GNA11 (19p13.3) seen in FHH type 2 (OMIM # 145981) or more rarely AP2S1 (19q13.2-q13.3) seen in FHH type 3 (OMIM # 600740).…”

Section: Fhhmentioning

confidence: 99%

Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES)

Iacobone

Carnaille

Palazzo

et al. 2015

Langenbecks Arch Surg

107

126

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Hereditary hyperparathyroidism typically presents at an earlier age than the sporadic variants. Gene penetrance and expressivity varies. Parathyroid multiple gland involvement is common, but in some variants, it may occur metachronously often with long disease-free intervals, simulating a single-gland involvement. Bilateral neck exploration with subtotal parathyroidectomy or total parathyroidectomy + autotransplantation should be performed, especially in MEN 1, in order to decrease the persistent and recurrent hyperparathyroidism rates; in some variants (MEN 2A, HPT-JT), limited parathyroidectomy can achieve long-term normocalcemia. In FHH, surgery is contraindicated; in NSHPT, urgent total parathyroidectomy is required. In FIHPT, MEN 4 and ADMH, a tailored case-specific approach is recommended.

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“…Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelong elevations of serum calcium concentrations in association with normal or mildly raised serum parathyroid hormone (PTH) concentrations in 80% of patients and low urinary calcium excretion (urinary calcium‐to‐creatinine clearance ratio <0.01) in 80% of patients 1, 2. FHH may be inherited as an autosomal dominant condition, and it is a genetically heterogeneous disorder with three recognized variants, FHH1‐3.…”

Section: Introductionmentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).

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Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism

Cited by 123 publications

References 91 publications

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

Roles of intraloops‐2 and ‐3 and the proximal C‐terminus in signalling pathway selection from the human calcium‐sensing receptor

Hereditary hyperparathyroidism—a consensus report of the European Society of Endocrine Surgeons (ESES)

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

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