Activating Mutations of the Calcium-Sensing Receptor: Management of Hypocalcemia

Lienhardt, Anne; Bai, Ming; Lagarde, Jean‐Pierre; Rigaud, M.; Zhang, Zaixiang; Jiang, Yougfeng; Kottler, Marie‐Laure; Brown, Edward M.; Garabédian, M

doi:10.1210/jcem.86.11.8016

Cited by 114 publications

(63 citation statements)

References 50 publications

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“…In a strict sense, this is not a state of HypoPT, as the parathyroid glands are well preserved although less responsive to a hypocalcaemic challenge (94). The CASR is also expressed in the renal tubule, and renal calcium excretion is often markedly increased in patients with ADH who are at increased risk of renal complications (56,95). In case reports, thiazide diuretics have been reported to reduce urinary calcium in patients with ADH (39,81,96).…”

Section: Special Circumstancesmentioning

confidence: 99%

European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults

Bollerslev¹,

Rejnmark²,

Marcocci³

et al. 2015

European Journal of Endocrinology

385

411

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Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors. (2015) 173, G1-G20 European Journal of Endocrinology Summary of recommendationsThe recommendations are worded as recommend (strong recommendation) and suggest (weak recommendation). We formally graded only the evidence underlying recommendations for therapeutic choices and target calcium levels. The quality of evidence behind the recommendations is classified as very low (4BBB), low (44BB), moderate (444B) and strong (4444). See further section 'Summary of methods used for guideline development'. European Journal of EndocrinologyClinical Practice Guideline J Bollerslev, L Rejnmark and others ESE guideline on treatment of chronic HypoPT

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Section: Special Circumstancesmentioning

confidence: 99%

European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults

Bollerslev¹,

Rejnmark²,

Marcocci³

et al. 2015

European Journal of Endocrinology

385

411

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“…Treatment with vitamin D metabolites fails to bring the serum calcium up toward the lower limit of normal, whereas calcium excretion is excessively stimulated potentially leading to nephrocalcinosis, nephrolithiasis, and renal damage (44,45). With the demonstration of VDREs in the CASR gene, the mechanism underlying the exuberant hypercalciuric response to vitamin D metabolites in autosomal dominant hypocalcemia patients now becomes clearer.…”

Section: Human Casr P1 and P2 Promoters Are Active In Human Proximalmentioning

confidence: 99%

“…Vitamin D up-regulation of the renal CASR is likely to underlie the increased basal and vasopressinelicited water and urea permeabilities in the inner medullary cortical ducts of rats made hypercalcemic with dihydrotachysterol that mimics 1,25(OH) 2 D action (46). However, in autosomal dominant hypocalcemia patients with activating CASR gene mutations, the normal counter-regulatory mechanisms are clearly often insufficient to protect against the vitamin D-stimulated hypercalciuria leading to nephrocalcinosis (44,45).…”

Section: Human Casr P1 and P2 Promoters Are Active In Human Proximalmentioning

confidence: 99%

Human Calcium-sensing Receptor Gene

Canaff¹,

Hendy

2002

Journal of Biological Chemistry

359

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The calcium-sensing receptor (CASR) that plays a critical role in this process is a glycoprotein with a predicted topology of a large extracellular domain, a seven-transmembrane domain, and an intracellular tail (3). This G protein-coupled receptor is expressed most abundantly in the parathyroid chief cells, along the length of the kidney tubule, and in thyroid C-cells. The CASR is activated by elevations in extracellular calcium concentration, leading to inhibition of PTH secretion and renal calcium reabsorption (4).Potentially, two important regulators of CASR gene expression are extracellular calcium and 1,25(OH) 2 D. Two previous studies were unable to demonstrate an effect of extracellular calcium on parathyroid gland or whole kidney CASR mRNA in the rat in vivo (5,6). This lack of modulation of CASR expression might be expected, given the constraints placed upon the CASR in tissues such as parathyroid gland or kidney, where it plays an essential role as a calciostat to sense very small changes in extracellular calcium concentration. Even modest alterations in the extracellular calcium set-point (this being defined as the extracellular calcium concentration for halfmaximal stimulation of PTH secretion from the parathyroid gland or calcium reabsorption across the kidney tubule) brought about by changes in CASR synthesis could have major unwanted effects on overall calcium homeostasis.Previously, the effect of vitamin D status (depleted versus replete) and/or treatment with 1,25(OH) 2 D 3 on parathyroid and kidney CASR mRNA levels has been examined in rats. One

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“…Soon after the cloning of the CASR (4), heterozygous activating mutations within its gene were reported as a cause of familial hypoparathyroidism (5). The elucidation of the molecular basis of this form of familial hypoparathyroidism with a dominant inheritance pattern has revealed a distinct clinical entity among the various forms of hypoparathyroidism, autosomal dominant hypocalcemia (ADH; MIM #601198) (6,7). ADH is a rare inherited disease that occurs clinically at any point during life time.…”

Section: Introductionmentioning

confidence: 99%

“…The clinical presentation is variable, and the associated hypocalcemia is often asymptomatic. The biochemical features of this condition include typically mild-to-moderate, and occasionally more severe, hypocalcemia and hyperphosphatemia accompanied by a low or normal PTH serum level and often a paradoxically normal or elevated urinary calcium excretion rate despite a low serum calcium concentration (6,7,9).…”

Section: Introductionmentioning

confidence: 99%

Novel calcium-sensing receptor cytoplasmic tail deletion mutation causing autosomal dominant hypocalcemia: molecular and clinical study

Obermannová

Šumnı́k

Dušátková

et al. 2016

European Journal of Endocrinology

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Objective: Autosomal dominant hypocalcemia (ADH) is a rare disorder caused by activating mutations of the calcium-sensing receptor (CASR). The treatment of ADH patients with 1a-hydroxylated vitamin D derivatives can cause hypercalciuria leading to nephrocalcinosis. Design and methods: We studied a girl who presented with hypoparathyroidism and asymptomatic hypocalcemia at age 2.5 years. Mutations of CASR were investigated by DNA sequencing. Functional analyses of mutant and WT CASRs were done in transiently transfected human embryonic kidney (HEK293) cells. Results: The proband and her father are heterozygous for an eight-nucleotide deletion c.2703_2710delCCTTGGAG in the CASR encoding the intracellular domain of the protein. Transient expression of CASR constructs in kidney cells in vitro suggested greater cell surface expression of the mutant receptor with a left-shifted extracellular calcium dose-response curve relative to that of the WT receptor consistent with gain of function. Initial treatment of the patient with calcitriol led to increased urinary calcium excretion. Evaluation for mosaicism in the paternal grandparents of the proband was negative. Conclusions: We describe a novel naturally occurring deletion mutation within the CASR that apparently arose de novo in the father of the ADH proband. Functional analysis suggests that the cytoplasmic tail of the CASR contains determinants that regulate the attenuation of signal transduction. Early molecular analysis of the CASR gene in patients with isolated idiopathic hypoparathyroidism is recommended because of its relevance to clinical outcome and treatment choice. In ADH patients, calcium supplementation and low-dose cholecalciferol avoids hypocalcemic symptoms without compromising renal function.

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Activating Mutations of the Calcium-Sensing Receptor: Management of Hypocalcemia

Cited by 114 publications

References 50 publications

European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults

European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults

Human Calcium-sensing Receptor Gene

Novel calcium-sensing receptor cytoplasmic tail deletion mutation causing autosomal dominant hypocalcemia: molecular and clinical study

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