Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey

Raue, Friedhelm; Pichl, J.; Dörr, Helmuth-G.; Schnabel, Dirk; Heidemann, P; Hammersen, G.; Jaursch-Hancke, Cornelia; Santen, Reinhard; Schöfl, Christof; Wabitsch, Martin; Haag, Christine; Schulze, Egbert; Frank‐Raue, Karin

doi:10.1111/j.1365-2265.2011.04142.x

Cited by 81 publications

(84 citation statements)

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“…ADH1 patients have calcitropic phenotypes, such as hypocalcemia with inappropriately low or normal PTH concentrations and a relative hypercalciuria that is characterized by urinary calcium to creatinine ratios that are within or above the reference range,1, 8, 9 and mice with a gain‐of‐function CaSR mutation, that are representative of ADH1, have been reported to also have non‐calcitropic phenotypes such as cataracts 10. Although these features are similar to hypoparathyroidism, ADH1 is considered to represent a distinct disease entity from hypoparathyroidism, because affected individuals generally have PTH concentrations that are detectable and within the reference range 1, 8. Furthermore, ADH1 patients may also develop a Bartter‐like syndrome characterized by hypokalemic alkalosis, renal salt wasting, and hyperreninemic hyperaldosteronism,11, 12 and the use of active vitamin D metabolites to treat symptomatic ADH1 patients may result in the development of marked hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal impairment 1, 9.…”

Section: Introductionmentioning

confidence: 99%

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Piret

Gorvin

Pagnamenta

et al. 2016

Journal of Bone and Mineral Research

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Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain‐of‐function mutations of the G‐protein coupled calcium‐sensing receptor (CaSR), and ADH2 caused by germline gain‐of‐function mutations of G‐protein subunit α‐11 (Gα11). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole‐exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three‐dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C‐terminal α5 helix, which may affect G‐protein coupled receptor binding and G‐protein activation. In vitro functional expression of wild‐type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration‐response curve with a significantly (p < 0.0001) reduced mean half‐maximal concentration (EC50) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild‐type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain‐of‐function mutation. A novel His403Gln variant in transforming growth factor, beta‐induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain‐of‐function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C‐terminal region for G‐protein function and CaSR signal transduction. © 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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Section: Introductionmentioning

confidence: 99%

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Piret

Gorvin

Pagnamenta

et al. 2016

Journal of Bone and Mineral Research

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“…ADH patients have mild to moderate hypocalcemia with low to normal PTH levels and an inappropriately normal or high urinary calcium excretion (21). Patients suffer from symptoms of hypocalcemia, develop tissue calcifications especially in the brain and kidney (22,23,24) and sometimes show defects in bone mineralization (25). A single mutated CASR allele suffices to produce ADH and there is only one case in the literature with a homozygous activating CASR mutation (26).…”

Section: Mutations Causing Gain Of Casr Functionmentioning

confidence: 99%

“…ADH patients may be asymptomatic and hypocalcemia is only discovered incidentally (22). Hypocalcemia, however, may cause muscle weakness, cramps, seizures and cardiac arrhythmias, which require immediate therapy (22,24,95,96,97,98,99) and chronically may lead to cataract formation and calcification of the basal ganglia (24,98,99,100,101).…”

Section: Therapy Of Patients With Mutations Causing Gain Of Casr Funcmentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr¹,

Schnabel²,

Dörr³

et al. 2016

European Journal of Endocrinology

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The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper-or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper-and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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“…(5) More than 50 activating mutations of CaSR have been reported (CaSR database; http://www.CASRdb.mcgill. ca), located in the extracellular domain, (6)(7)(8)(9)(10)(11) the transmembrane domain, (10)(11)(12)(13)(14)(15) and the intracellular domain. (16) Gain-of-function mutations of CaSR result in an increase in the sensitivity of cells to the extracellular Ca 2þ .…”

Section: Introductionmentioning

confidence: 99%

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

Dong

Endo

Ohnishi

et al. 2015

Journal of Bone and Mineral Research

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Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D 3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca 2þ of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a novel therapeutic agent for ADH.

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Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey

Abstract: This series increases the limited knowledge of mutations and phenotypes of this rare disorder. Mutation analysis of the CaSR gene facilitates patient and family management. Low dosages of calcitriol resulted in less frequent renal calcifications.

Cited by 81 publications

References 22 publications

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

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