Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function Gα11 mutation

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Gorvin , C M , Hannan , F M , Cranston , T , Valta , H , Mäkitie , O , Schalin-Jäntti , C & Thakker , R V 2018 , ' Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function Gα11 mutation ' , Journal of Bone and Mineral Research , vol. 33 , no. 1 , pp. 32-41 . https://doi.org/10.1002/jbmr.3241

Title: Cinacalcet rectifies hypercalcemia in a patient with familial hypocalciuric hypercalcemia type 2 (FHH2) caused by a germline loss-of-function Gα11 mutation
Author: Gorvin, C.M.; Hannan, F.M.; Cranston, T.; Valta, Helena; Mäkitie, Outi; Schalin-Jäntti, Camilla; Thakker, R.V.
Contributor: University of Helsinki, Children's Hospital
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2018-01
Language: eng
Number of pages: 10
Belongs to series: Journal of Bone and Mineral Research
ISSN: 0884-0431
URI: http://hdl.handle.net/10138/231656
Abstract: G-protein subunit -11 (G(11)) couples the calcium-sensing receptor (CaSR) to phospholipase C (PLC)-mediated intracellular calcium (Ca-i(2+)) 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 G(11) mutations cause familial hypocalciuric hypercalcemia type 2 (FHH2), for which effective therapies are currently not available. Here, we report a novel heterozygous G(11) 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 G(11), 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 G(11) proteins into HEK293 cells, which express the CaSR, showed the mutant Ser220 G(11) protein to impair CaSR-mediated Ca-i(2+) 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 G(11) cleft region also impaired signaling by PLC. The loss-of-function associated with the Ser220 G(11) 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 G(11) mutation, normalized serum ionized calcium concentrations. Thus, our studies, which report a novel G(11) germline mutation (Phe220Ser) in a family with FHH2, reveal the importance of the G(11) 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. (c) 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Subject: ACTIVATION
BOVINE PARATHYROID CELLS
CALCIUM-SENSING RECEPTOR
CELL
COMPLEX
DISORDERS
DISORDERS OF CALCIUM
ENDOCRINE PATHWAYS
HEK293 CELLS
INSIGHTS
KINASE
PARATHYROID-RELATED DISORDERS
PHOSPHATE METABOLISM
PHOSPHOLIPASE-C
PROTEIN-COUPLED RECEPTORS
THERAPEUTICS
TISSUE SIGNALING
3121 General medicine, internal medicine and other clinical medicine
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