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

Obermannová, Barbora; Šumnı́k, Zdenĕk; Dušátková, Petra; Cinek, Ondřej; Grant, Michael; Lebl, Jan; Hendy, Geoffrey N.

doi:10.1530/eje-15-1216

Cited by 12 publications

(8 citation statements)

References 44 publications

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“…Indeed, two ubiquitin ligases, AMSH and dorfin, which reduce CaSR expression by increasing receptor degradation, have been demonstrated to bind to this region of the C-terminus (McCullough et al 2004, Huang et al 2006, and the ADH1 deletion mutants may increase CaSR signalling by reducing receptor degradation. Consistent with this idea, in vitro studies demonstrated that cells expressing the Ser895fsX939 and Ser901-904fsX977 mutants exhibited elevated levels of CaSR protein and increased Ca 2+ i and MAPK signalling when compared to cells expressing WT CaSR (Lienhardt et al 2000, Obermannova et al 2016, Maruca et al 2017. This occurs despite loss of the region identified to bind filamin-A, an actin cytoskeletal protein that enhances CaSR-mediated activation of MAPK pathways (Zhang & Breitwieser 2005).…”

Section: Genetic Landscape Of Adh1mentioning

confidence: 71%

Molecular and clinical insights from studies of calcium-sensing receptor mutations

Gorvin

2019

Journal of Molecular Endocrinology

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Twenty-five years have elapsed since the calcium-sensing receptor (CaSR) was first identified in bovine parathyroid and the receptor is now recognized as a fundamental contributor to extracellular Ca 2+ (Ca 2+ e ) homeostasis, regulating parathyroid hormone release and urinary calcium excretion. The CaSR is a class C G-protein-coupled receptor (GPCR) that is functionally active as a homodimer and couples to multiple G-protein subtypes to activate intracellular signalling pathways. The importance of the CaSR in the regulation of Ca 2+ e has been highlighted by the identification of >400 different germline loss-and gain-of-function CaSR mutations that give rise to disorders of Ca 2+ e homeostasis. CaSR-inactivating mutations cause neonatal severe hyperparathyroidism, characterised by marked hypercalcaemia, skeletal demineralisation and failure to thrive in early infancy; and familial hypocalciuric hypercalcaemia, an often asymptomatic disorder associated with mild-moderately elevated serum calcium concentrations. Activating mutations are associated with autosomal dominant hypocalcaemia, which is occasionally associated with a Bartter's-like phenotype. Recent elucidation of the CaSR extracellular domain structure enabled the locations of CaSR mutations to be mapped and has revealed clustering in locations important for structural integrity, receptor dimerisation and ligand binding. Moreover, the study of disease-causing mutations has demonstrated that CaSR signals in a biased manner and have revealed specific residues important for receptor activation. This review presents the current understanding of the genetic landscape of CaSR mutations by summarising findings from clinical and functional studies of diseaseassociated mutations. It concludes with reflections on how recently uncovered signalling pathways may expand the understanding of calcium homeostasis disorders.

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Section: Genetic Landscape Of Adh1mentioning

confidence: 71%

Molecular and clinical insights from studies of calcium-sensing receptor mutations

Gorvin

2019

Journal of Molecular Endocrinology

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“…There is a tendancy for hypomagnesemia. This syndrome is linked to gain-of-function, or activating, mutations of the CASR gene [40–42].

50% of patients present with moderate and asymptomatic hypocalcemia that is found fortuitously,

50% present with paresthesias, tetany, epilepsy, severe hypocalcaemia, sometimes with Bartter syndrome [43],

10% present with hypercalciuria with nephrocalcinosis or lithiasis,

Over 35% present with ectopic and/or basal ganglia calcifications.

…”

Section: Genetic Causesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

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“…To date, more than 100 germline activating mutations in GPCR genes have been reported (Table and Figure ). Of these, more than 70 were detected in CASR . Patients with GPCR gain‐of‐function mutations manifest inappropriate hormone secretion or function that reflects excessive receptor activity (Table ).…”

Section: Gpcr Mutations and Disordersmentioning

confidence: 99%

“…The N‐terminal domain, the third intracellular loop and the sixth transmembrane domain appear to be hot spots for gain‐of‐function missense mutations (Figure ) . In addition, inframe deletions in CASR and TSHR , as well as frameshift mutations in CASR and PROKR2 have been documented to exert gain‐of‐function effects . Relatively large N‐ and C‐terminal domains of CASR likely provide hot spots for gain‐of‐function mutations (Figure ).…”

Section: Nucleotide Alterations Leading To Gpcr Gain‐of‐functionmentioning

confidence: 99%

Gain‐of‐function mutations in G‐protein–coupled receptor genes associated with human endocrine disorders

Fukami

Suzuki

Igarashi

et al. 2017

Clinical Endocrinology

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SummaryThe human genome encodes more than 700 G-protein-coupled receptors (GPCRs), many of which are involved in hormone secretion. To date, more than 100 gain-offunction (activating) mutations in at least ten genes for GPCRs, in addition to several loss-of-function mutations, have been implicated in human endocrine disorders.Previously reported gain-of-function GPCR mutations comprise various missense substitutions, frameshift mutations, intragenic inframe deletions and copy-number gains.

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

Cited by 12 publications

References 44 publications

Molecular and clinical insights from studies of calcium-sensing receptor mutations

Molecular and clinical insights from studies of calcium-sensing receptor mutations

Diseases associated with calcium-sensing receptor

Gain‐of‐function mutations in G‐protein–coupled receptor genes associated with human endocrine disorders

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