Functional Deletion of the Calcium-Sensing Receptor in a Case of Neonatal Severe Hyperparathyroidism

Ward, Bryan K.; Magno, Aaron L.; Davis, Elizabeth A.; Hanyaloglu, Aylin C.; Stuckey, Bronwyn; Burrows, Mark; Eidne, Karin A.; Charles, Adrian; Ratajczak, Thomas

doi:10.1210/jc.2003-031653

Cited by 39 publications

(50 citation statements)

References 31 publications

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“…and CaR R648X (22). While CaR G94X exhibited no membrane expression, as for CaR R392X in the current study, CaR R648X did achieve membrane localisation as it includes the first transmembrane span.…”

Section: G94xsupporting

confidence: 49%

“…Nevertheless, neither mutant CaR was functional resulting in NSHPT in which the child also exhibited impaired brain development at 4 months. In contrast, the proband in the current case, who had a parathyroidectomy in her second month, had a normal head CT scan at age 4 years and exhibits above average intelligence at age 11 years, adding weight to the idea that it may not be the total absence of functional CaR per se that causes the neurological impairment associated with some cases of NSHPT but prolonged hypercalcaemia (22,23,24).…”

Section: G94xmentioning

confidence: 62%

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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’

Ward

Mughal

Ranieri

et al. 2013

European Journal of Endocrinology

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Objective: Loss-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 (CaR R392X ), in effect a full CAR 'knockout'. Case report: The 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 methods: The R392X stop codon was inserted into human CAR and the resulting mutant (CaR R392X ) expressed transiently in HEK-293 cells. Results: CaR R392X 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 CaR R392X -transfected cells. Expression of the mutant was localised to endoplasmic reticulum consistent with its lack of functional activity. Conclusions: Intriguingly, 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 Ca 2C supplementation. Despite representing a virtual CAR knockout, the patient displays no obvious pathologies beyond her calcium homeostatic dysfunction.

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Section: G94xsupporting

confidence: 49%

Section: G94xmentioning

confidence: 62%

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’

Ward

Mughal

Ranieri

et al. 2013

European Journal of Endocrinology

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“…It could be hypothesized that distinct, biochemically defined binding site(s) for Sr o 2ϩ and Ca o 2ϩ exist within the extracellular domain of the CaR that would activate different signaling pathways upon binding of the respective ions to the receptor. Indeed, the CaR is known to activate multiple G proteins involved in distinct signaling pathways (35). The CaR couples to G␣ i , which inhibits activation of adenylate cyclase, to G␣ q , which stimulates PLC, to G␣ 12/13 , which stimulate phospholipase D, and to the formation of G ␤ ␥ subunits, which stimulate phosphatidyl- The targeting of Sr o 2ϩ to bone mineral could confer upon this agent a specific and direct action on osteoclasts out of proportion to its circulating level.…”

Section: Discussionmentioning

confidence: 99%

The Calcium-sensing Receptor Is Involved in Strontium Ranelate-induced Osteoclast Apoptosis

Hurtel-Lemaire

Mentaverri

Caudrillier

et al. 2009

Journal of Biological Chemistry

223

126

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“…However, no phenotype/genotype correlation was found, as demonstrated by Waller et al [5] who reported that the clinical outcome differed between patients from the same family even after a similar homozygous mutation. Moreover, a functional deletion of the CaSR was reported in a case of severe neonatal HP1 [6]. …”

Section: Discussionmentioning

confidence: 99%

Primary Hyperparathyroidism in Neonates and Childhood

Mallet¹

2008

Horm Res Paediatr

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Objectives: Primary hyperparathyroidism (HP1) in childhood is thought to be extremely rare. Its exact incidence remains unknown, as do the characteristics of HP1. A retrospective study collection was conducted on cases supplied by members of the Working Group on Calcium Metabolism throughout France over a 20-year period (1984–2004), since the availability of the intact parathormone (iPTH) radioimmunoassay. Results: 55 cases were collected of which 11 were neonates. Among the 44 children and adolescents, there were 18 male and 26 female patients, ranging in age from 6 to 18 (mean 13) years. 83% were symptomatic and 43% had nephrolithiasis. Symptoms were associated with high serum calcium and inappropriate iPTH levels. Ultrasonography and technetium-labelled methoxyisobutylisonitrile scintigraphy are useful tools for the preoperative localization of adenomas, particularly in adolescents. Intraoperative iPTH assays are effective in minimizing invasive parathyroidectomy. All patients, except neonates, underwent surgery: 29 adenomas and 11 hyperplasias were found. Two multiple endocrine neoplasias (MENs) were subsequently discovered. Since the calcium-sensing receptor (CaSR) mutation was reported, the form of management in neonates has become more medical (intravenous diphosphonates) than surgical. On follow-up no recurrence was observed except for MEN. Conclusion: These national results reflect HP1 epidemiology. HP1 is a rare entity and appears to be a severe disease in terms of symptoms with regard to management. The use of molecular biology tests could be useful not only in neonatal cases (CaSR mutation) but also prior to surgery in children (MEN mutation).

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Functional Deletion of the Calcium-Sensing Receptor in a Case of Neonatal Severe Hyperparathyroidism

Cited by 39 publications

References 31 publications

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’

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’

The Calcium-sensing Receptor Is Involved in Strontium Ranelate-induced Osteoclast Apoptosis

Primary Hyperparathyroidism in Neonates and Childhood

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