title: Knockin mouse with mutant Gα11mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors.
abstract: Heterotrimeric G proteins play critical roles in transducing extracellular signals generated by 7-transmembrane domain receptors. Somatic gain-of-function mutations in G protein α subunits are associated with a variety of diseases. Recently, we identified gain-of-function mutations in Gα11in patients with autosomal-dominant hypocalcemia type 2 (ADH2), an inherited disorder of hypocalcemia, low parathyroid hormone (PTH), and hyperphosphatemia. We have generated knockin mice harboring the point mutationGNA11c.C178T (p.Arg60Cys) identified in ADH2 patients. The mutant mice faithfully replicated human ADH2. They also exhibited low bone mineral density and increased skin pigmentation. Treatment with NPS 2143, a negative allosteric modulator of the calcium-sensing receptor (CASR), increased PTH and calcium concentrations in WT and mutant mice, suggesting that the gain-of-function effect of GNA11R6OCis partly dependent on coupling to the CASR. Treatment with the Gα11/q-specific inhibitor YM-254890 increased blood calcium in heterozygous but not in homozygousGNA11R60Cmice, consistent with published crystal structure data showing that Arg60 forms a critical contact with YM-254890. This animal model of ADH2 provides insights into molecular mechanism of this G protein-related disease and potential paths toward new lines of therapy.
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Roszko
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Ruiye
authors.initials: R
authors.lastname: Bi
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, England, United Kingdom.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Gorvin
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Xiong
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.|Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, England, United Kingdom.
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gardella
authors.affiliation: Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mannstadt
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D053565:Hypercalciuria / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006996:Hypocalcemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D007011:Hypoparathyroidism / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009281:Naphthalenes / Q000008:administration & dosage* / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage* / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism
chemical_list: C577923:CASR protein, mouse; C000608020:GNA11 protein, mouse; D044385:GTP-Binding Protein alpha Subunits; C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D010281:Parathyroid Hormone; D010456:Peptides, Cyclic; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; C475455:YM-254890; D002118:Calcium