Codon Arg15 Mutations of the<i>AP2S1</i>Gene: Common Occurrence in Familial Hypocalciuric Hypercalcemia Cases Negative for Calcium-Sensing Receptor (<i>CASR</i>) Mutations

Hendy, Geoffrey N.; Canaff, Lucie; Newfield, Ron S.; Tripto-Shkolnik, Liana; Wong, Betty; Lee, Bonnie S. P.; Cole, David E. C.

doi:10.1210/jc.2014-1120

Cited by 43 publications

(31 citation statements)

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“…AP2s has a pivotal role in clathrin-mediated endocytosis of GPCRs such as the CaSR, and to date more than 50 FHH3 patients with AP2s mutations, which are all missense mutations involving the Arg15 residue (Arg15Cys, Arg15His and Arg15Leu), have been reported. (12)(13)(14)(15)(16) Approximately 65% of FHH patients will have a CaSR mutation, 5% an AP2s mutation, <1% a Ga 11 mutation, and the remaining $30% of FHH patients are considered to have involvement of a genetic abnormality that remains to be identified. Here we report the identification of a novel Ga 11 mutation in a patient with FHH in whom CaSR and AP2s mutations had been previously excluded.…”

Section: ) With Rapid Increase In Intracellular Calciummentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogeneous disorder with three variants, FHH1 to FHH3. FHH1 is caused by loss‐of‐function mutations of the calcium‐sensing receptor (CaSR), a G‐protein coupled receptor that predominantly signals via G‐protein subunit alpha‐11 (Gα11) to regulate calcium homeostasis. FHH2 is the result of loss‐of‐function mutations in Gα11, encoded by GNA11, and to date only two FHH2‐associated Gα11 missense mutations (Leu135Gln and Ile200del) have been reported. FHH3 is the result of loss‐of‐function mutations of the adaptor protein‐2 σ‐subunit (AP2σ), which plays a pivotal role in clathrin‐mediated endocytosis. We describe a 65‐year‐old woman who had hypercalcemia with normal circulating parathyroid hormone concentrations and hypocalciuria, features consistent with FHH, but she did not have CaSR and AP2σ mutations. Mutational analysis of the GNA11 gene was therefore undertaken, using leucocyte DNA, and this identified a novel heterozygous GNA11 mutation (c.161C>T; p.Thr54Met). The effect of the Gα11 variant was assessed by homology modeling of the related Gαq protein and by measuring the CaSR‐mediated intracellular calcium (Ca2+ i) responses of HEK293 cells, stably expressing CaSR, to alterations in extracellular calcium (Ca2+ o) using flow cytometry. Three‐dimensional modeling revealed the Thr54Met mutation to be located at the interface between the Gα11 helical and GTPase domains, and to likely impair GDP binding and interdomain interactions. Expression of wild‐type and the mutant Gα11 in HEK293 cells stably expressing CaSR demonstrate that the Ca2+ i responses after stimulation with Ca2+ o of the mutant Met54 Gα11 led to a rightward shift of the concentration‐response curve with a significantly (p < 0.01) increased mean half‐maximal concentration (EC50) value of 3.88 mM (95% confidence interval [CI] 3.76–4.01 mM), when compared with the wild‐type EC50 of 2.94 mM (95% CI 2.81–3.07 mM) consistent with a loss‐of‐function. Thus, our studies have identified a third Gα11 mutation (Thr54Met) causing FHH2 and reveal a critical role for the Gα11 interdomain interface in CaSR signaling and Ca2+ o homeostasis. © 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: ) With Rapid Increase In Intracellular Calciummentioning

confidence: 99%

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Gorvin

Cranston

Hannan

et al. 2016

Journal of Bone and Mineral Research

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“…FHH-2 and FHH-3 are associated, respectively, with germline inactivating mutations of GNA11 (19p13.3) and AP2S1 (19q13.2) genes 13 32 88 90 91 141 185 . GNA11 gene encodes the α-subunit of G 11 , one of the principal G proteins activating CaSR signalling pathway, whereas AP2S1 gene encodes the adaptor protein 2 σ-subunit involved in CaSR endocytosis 13 32 88 90 91 141 185. Both mutations in GNA11 and AP2S1 genes cause hypocalciuric hypercalcaemia though aberrant inactivation of CaSR signalling, similar to FHH-1 13 32 88 90 91 141 185.…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

“…GNA11 gene encodes the α-subunit of G 11 , one of the principal G proteins activating CaSR signalling pathway, whereas AP2S1 gene encodes the adaptor protein 2 σ-subunit involved in CaSR endocytosis 13 32 88 90 91 141 185. Both mutations in GNA11 and AP2S1 genes cause hypocalciuric hypercalcaemia though aberrant inactivation of CaSR signalling, similar to FHH-1 13 32 88 90 91 141 185. Phenotypically and pathologically, patients with FHH-2 typically present with features indistinguishable from FHH-1, whereas those with FHH-3 tend to present with osteomalacia, higher levels of PTH and more frequent parathyroid gland involvement (hyperplasia) 3 13 32 42 88 90 91 141 185…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

Clinicopathological correlates of hyperparathyroidism

2015

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Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

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“…Homozygous CASR mutations leading to only a mild overall impairment of extracellular calcium sensing may cause a FHH-like phenotype (8,12,13,14), whereas heterozygous CASR mutations causing more pronounced functional impairment can lead to neonatal hyperparathyroidism (NHPT) (15,16,17). Recently it has been found that inactivating mutations in the CASR associated G protein alpha 11 (GNA11) and in the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) can also cause familial hypocalciuric hypercalcemia (FHH types 2 and 3) (18,19,20).…”

Section: Mutations Causing Loss Of Casr Functionmentioning

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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Codon Arg15 Mutations of theAP2S1Gene: Common Occurrence in Familial Hypocalciuric Hypercalcemia Cases Negative for Calcium-Sensing Receptor (CASR) Mutations

Cited by 43 publications

References 19 publications

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

A G-protein Subunit-α11 Loss-of-Function Mutation, Thr54Met, Causes Familial Hypocalciuric Hypercalcemia Type 2 (FHH2)

Clinicopathological correlates of hyperparathyroidism

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

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