Calcium-sensing receptor mutations and denaturing high performance liquid chromatography

Cole, David E. C.; Yun, Francisco; Wong, Betty; Shuen, Andrew Y.; Booth, Ronald A.; Scillitani, Alfredo; Pidasheva, Svetlana; Zhou, Xiang; Canaff, Lucie; Hendy, Geoffrey N.

doi:10.1677/jme-08-0164

Cited by 35 publications

(24 citation statements)

References 40 publications

(31 reference statements)

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“…The missense variant c.682G>A (p.Glu228Lys; p. E228K) identified in our patient has previously been reported in the literature [14]. That patient, a male infant, presented at 10 weeks of age with seizures, tetany and a positive Chvostek sign.…”

Section: Discussionsupporting

confidence: 58%

“…On molecular genetic analysis, our patient was found to have a de novo missense variant, c.682G>A (p.Glu228Lys) in exon 4 of CASR , confirming the diagnosis of ADH. This mutation has previously been reported in the literature [14]. The analysis could not exclude the rare possibility that the parents are mosaic for the variant and therefore at risk of developing some symptoms.…”

Section: Case Illustrationmentioning

confidence: 96%

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Anticonvulsant Treatment Associated with Intractable Hypocalcaemia in a Female Child with Hypoparathyroidism

et al. 2014

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Background: We report the case of a female infant with hypoparathyroidism due to an activating mutation in the calcium-sensing receptor gene. Case Report: The child presented in the neonatal period with clinical seizures associated with severe hypocalcaemia, hyperphosphataemia, low parathyroid hormone levels and elevated urine calcium:creatinine ratios. She required intravenous calcium and phenobarbitone initially, and then oral 1-alfacalcidol (1-AC) and phenobarbitone were started. The patient had intractable hypocalcaemia in the first 5 months of life despite escalating doses of 1-AC. When the phenobarbitone was stopped at 5 months of age she was admitted soon after with symptomatic hypercalcaemia. We postulate that the phenobarbitone increased the metabolism of 1-AC and thus she needed large doses of 1-AC to treat hypocalcaemia until the phenobarbitone was stopped. Her parents had no biochemical abnormalities on testing. Results: Molecular genetic analysis confirmed that our patient had a de novo missense variant, c.682G>A (p.Glu228Lys) in exon 4 of the calcium-sensing receptor. Conclusion: This case report highlights the importance that clinicians caring for children on vitamin D and its analogues are aware of the interaction with phenobarbitone, which can result in symptomatic hypocalcaemia. 1-AC should be stored at 2-8°C, otherwise it will be rendered inactive.

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Section: Discussionsupporting

confidence: 58%

Section: Case Illustrationmentioning

confidence: 96%

Anticonvulsant Treatment Associated with Intractable Hypocalcaemia in a Female Child with Hypoparathyroidism

et al. 2014

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“…Although absent in the GABA B receptor, several lines of evidence highlight the crucial role of the CRD in the allosteric connection between the VFT and the 7TM in the other class C GPCRs. First, genetic mutations of cysteines in mGlu6 and CaSR CRDs have been identified in human diseases, such as "night blindness" (19) and "hypocalciuric hypercalcemia" (20)(21)(22), respectively. Second, deletion of the CRD in mGluRs results in a loss of function (23).…”

mentioning

confidence: 99%

Interdomain movements in metabotropic glutamate receptor activation

Huang

Cao

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Many cell surface receptors are multimeric proteins, composed of several structural domains, some involved in ligand recognition, whereas others are responsible for signal transduction. In most cases, the mechanism of how ligand interaction in the extracellular domains leads to the activation of effector domains remains largely unknown. Here we examined how the extracellular ligand binding to the venus flytrap (VFT) domains of the dimeric metabotropic glutamate receptors activate the seven transmembrane (7TM) domains responsible for G protein activation. These two domains are interconnected by a cysteine-rich domain (CRD). We show that any of the four disulfide bridges of the CRD are required for the allosteric coupling between the VFT and the 7TM domains. More importantly, we show that a specific association of the two CRDs corresponds to the active state of the receptor. Indeed, a specific crosslinking of the CRDs with intersubunit disulfide bridges leads to fully constitutively active receptors, no longer activated by agonists nor by allosteric modulators. These data demonstrate that intersubunit movement at the level of the CRDs represents a key step in metabotropic glutamate receptor activation.transmembrane signaling | G protein-coupled receptor | allosteric modulation M ost cell surface receptors are multimeric complexes of which each subunit is produced through the association of different domains throughout evolution (1-5). The activation of such receptor complexes is a result of coordinated conformational changes or movement of these different domains. Although an increasing amount of 3D crystal structures are becoming available, there is still limited information available on the structural basis of interdomain communication.Class C G protein-coupled receptors (GPCRs) represent key examples of such receptor complexes (6, 7). These receptors are obligatory dimers, either homo-or heterodimers, made by the association of two domains over evolutionary time; an extracellular bilobate venus flytrap (VFT) domain associated with a G protein activating 7 transmembrane (7TM) domain (Fig. 1A) (8). The VFTs are evolved from certain types of bacterial periplasmic binding proteins, especially those of the leucine-isoleucinevaline binding protein family involved in the transport of amino acids, sugars, or ions. Not surprisingly, class C GPCRs are activated by amino acids, i.e., the receptors for the two major neurotransmitters, the eight metabotropic glutamate receptors (mGluRs), and the GABA B receptor; sugar (the sweet taste receptors); or ions [the calcium-sensing receptor (CaSR)]. Accordingly, class C GPCRs represent exciting new targets for drug development for both the pharmaceutical and food industries, as illustrated by the number of drugs targeting these receptors already on the market (the GABA B receptor agonist baclofen, umami compounds, and various sweeteners such as aspartame, and cinacalcet, a positive allosteric modulator of the CaSR), and those in clinical trials (9-11).The precise mechanisms of how...

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“…CASR testing, with functional analysis, provides valuable evidence in the differential diagnosis of hypercalcaemic states, as recently published (20). New technologies such as denaturing HPLC provide a rapid and effective tool to screen for CASR mutations (21).…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

Al‐Salameh

Cetani²,

Pardi³

et al. 2011

European Journal of Endocrinology

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Objective: The calcium-sensing receptor (CASR) has an important role in calcium homoeostasis by controlling PTH secretion and renal calcium handling. Inactivating mutations in the CASR gene (HGNC ID: 1514) cause familial hypocalciuric hypercalcaemia (FHH). We present a case of FHH patient to describe a novel mutation in the CASR. Subjects and methods: A 34-year-old patient was referred because of recurrent hypercalcaemia after resection of two hyperplastic parathyroids. Extensive evaluation found elevated PTH and low calcium/creatinine clearance ratio. One of her three children had high serum calcium concentrations. Genetic studies were performed by PCR amplification of CASR coding exons and direct sequencing of PCR products. Transient transfection of the wild-type (WT) CASR and the mutant CASR into COS-7 was performed to assess functional impact of the mutation and the capacity of either protein to mediate increases in cellular levels of inositol phosphates (IPs). Results: CASR sequencing found a previously undescribed heterozygous base substitution, determining a change of threonine to isoleucine at codon 550 (p.T550I) in the sixth exon. In contrast to those transfected with WT CASR, which showed a five-to eightfold increase in total IPs at high levels of calcium, COS-7 cells transfected with the (p.T550I) mutant showed no increase confirming to the inactivating nature of the mutation. COS-7 cells co-transfected with the WT and the (p.T550I) mutant showed an intermediate response suggesting a possible dominant negative effect. Conclusion: This case report presents a not-yet-described mutation in the cysteine-rich region of the CASR extracellular domain, a mutation with a possible dominant negative effect.

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Calcium-sensing receptor mutations and denaturing high performance liquid chromatography

Cited by 35 publications

References 40 publications

Anticonvulsant Treatment Associated with Intractable Hypocalcaemia in a Female Child with Hypoparathyroidism

Anticonvulsant Treatment Associated with Intractable Hypocalcaemia in a Female Child with Hypoparathyroidism

Interdomain movements in metabotropic glutamate receptor activation

A novel mutation in the calcium-sensing receptor in a French family with familial hypocalciuric hypercalcaemia

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