Cinacalcet for Symptomatic Hypercalcemia Caused by <i>AP2S1</i> Mutations

Howles, Sarah; Hannan, Fadil; Babinsky, Valerie; Rogers, Alice; Gorvin, Caroline M; Rust, Nigel; Richardson, Tristan; McKenna, Malachi J.; Nesbit, M. Andrew

doi:10.1056/nejmc1511646

Cited by 47 publications

(57 citation statements)

References 5 publications

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“…Positive allosteric modulators of the CaSR, known as calcimimetics, represent a targeted therapy for patients with symptomatic FHH. Indeed, cinacalcet, a licensed calcimimetic drug, has been used to ameliorate symptomatic hypercalcemia in patients with FHH1 and FHH3 . However, such effects of cinacalcet in FHH2 patients have not been reported, although cinacalcet has been shown in vitro, to rectify signaling abnormalities associated with FHH2‐causing Gα 11 mutations .…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, cinacalcet, a licensed calcimimetic drug, has been used to ameliorate symptomatic hypercalcemia in patients with FHH1 and FHH3. (7)(8)(9) However, such effects of cinacalcet in FHH2 patients have not been reported, although cinacalcet has been shown in vitro, to rectify signaling abnormalities associated with FHH2-causing Ga 11 mutations. (10) Here, we report the effectiveness of cinacalcet in ameliorating the signaling defects and hypercalcemia due to a previously unreported FHH2-associated Ga 11 mutation, Phe220Ser.…”

Section: Introductionmentioning

confidence: 99%

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Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

Gorvin

Hannan

Cranston

et al. 2017

Journal of Bone and Mineral Research

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G‐protein subunit α‐11 (Gα11) couples the calcium‐sensing receptor (CaSR) to phospholipase C (PLC)‐mediated intracellular calcium (Ca2+ i) and mitogen‐activated protein kinase (MAPK) signaling, which in the parathyroid glands and kidneys regulates parathyroid hormone release and urinary calcium excretion, respectively. Heterozygous germline loss‐of‐function Gα11 mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous Gα11 germline mutation, Phe220Ser, which was associated with hypercalcemia in a family with FHH2. Homology modeling showed the wild‐type (WT) Phe220 nonpolar residue to form part of a cluster of hydrophobic residues within a highly conserved cleft region of Gα11, which binds to and activates PLC; and predicted that substitution of Phe220 with the mutant Ser220 polar hydrophilic residue would disrupt PLC‐mediated signaling. In vitro studies involving transient transfection of WT and mutant Gα11 proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 Gα11 protein to impair CaSR‐mediated Ca2+ i and extracellular signal‐regulated kinase 1/2 (ERK) MAPK signaling, consistent with diminished activation of PLC. Furthermore, engineered mutagenesis studies demonstrated that loss of hydrophobicity within the Gα11 cleft region also impaired signaling by PLC. The loss‐of‐function associated with the Ser220 Gα11 mutant was rectified by treatment of cells with cinacalcet, which is a CaSR‐positive allosteric modulator. Furthermore, in vivo administration of cinacalcet to the proband harboring the Phe220Ser Gα11 mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel Gα11 germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the Gα11 hydrophobic cleft region for CaSR‐mediated activation of PLC, and show that allosteric CaSR modulation can rectify the loss‐of‐function Phe220Ser mutation and ameliorate the hypercalcemia associated with FHH2. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

Gorvin

Hannan

Cranston

et al. 2017

Journal of Bone and Mineral Research

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“…Cinacalcet has also been evaluated as a therapy for symptomatic hypercalcaemia associated with FHH3. In vitro studies revealed this calcimimetic to rectify the loss‐of‐function associated with all three reported FHH3‐causing AP2σ mutations (Table ) (Howles et al ., ). Indeed, administration of 10 nM cinacalcet corrected the impaired Ca 2+ i and MAPK signalling responses of HEK–CaS receptor cells expressing Arg 15 Cys, Arg 15 His or Arg 15 Leu AP2σ mutant proteins (Howles et al ., ).…”

Section: Calcimimetic Treatment For Hypercalcaemic Disorders Of the Cmentioning

confidence: 97%

“…In vitro studies revealed this calcimimetic to rectify the loss‐of‐function associated with all three reported FHH3‐causing AP2σ mutations (Table ) (Howles et al ., ). Indeed, administration of 10 nM cinacalcet corrected the impaired Ca 2+ i and MAPK signalling responses of HEK–CaS receptor cells expressing Arg 15 Cys, Arg 15 His or Arg 15 Leu AP2σ mutant proteins (Howles et al ., ). In vivo , cinacalcet has been administered to three FHH3 patients, who each harboured a heterozygous Arg 15 Cys, Arg 15 His or Arg 15 Leu AP2σ mutation and had symptoms such as fatigue, musculoskeletal pain and headaches (Howles et al ., ).…”

Section: Calcimimetic Treatment For Hypercalcaemic Disorders Of the Cmentioning

confidence: 97%

Calcimimetic and calcilytic therapies for inherited disorders of the calcium‐sensing receptor signalling pathway

Hannan

Olesen

Thakker

2017

British J Pharmacology

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“…Howles et al . [9] have shown the efficacy of cinacalcet in patients with familial hypocalciuric hypercalcemia harboring the AP2S1 mutations.…”

mentioning

confidence: 99%

Utility of cinacalcet in familial hypocalciuric hypercalcemia

Kelwade

et al. 2017

Indian J Endocr Metab

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Cinacalcet for Symptomatic Hypercalcemia Caused by AP2S1 Mutations

Cited by 47 publications

References 5 publications

Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

Cinacalcet Rectifies Hypercalcemia in a Patient With Familial Hypocalciuric Hypercalcemia Type 2 (FHH2) Caused by a Germline Loss-of-Function Gα11 Mutation

Calcimimetic and calcilytic therapies for inherited disorders of the calcium‐sensing receptor signalling pathway

Utility of cinacalcet in familial hypocalciuric hypercalcemia

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