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

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