title: Gα11mutation in mice causes hypocalcemia rectifiable by calcilytic therapy.
abstract: Heterozygous germline gain-of-function mutations of G-protein subunit α11(Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in autosomal dominant hypocalcemia type 2 (ADH2). ADH2 may cause symptomatic hypocalcemia with low circulating parathyroid hormone (PTH) concentrations. Effective therapies for ADH2 are currently not available, and a mouse model for ADH2 would help in assessment of potential therapies. We hypothesized that a previously reported dark skin mouse mutant (Dsk7) - which has a germline hypermorphic Gα11mutation, Ile62Val - may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. MutantDsk7/+andDsk7/Dsk7mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 Gα11to upregulate CaSR-mediated intracellular calcium and MAPK signaling, consistent with a gain of function. Treatment with NPS-2143, a calcilytic compound, normalized these signaling responses. In vivo, NPS-2143 induced a rapid and marked rise in plasma PTH and calcium concentrations inDsk7/Dsk7andDsk7/+mice, which became normocalcemic. Thus, these studies have establishedDsk7mice, which harbor a germline gain-of-function Gα11mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Gorvin
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.|Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Fadil M
authors.initials: FM
authors.lastname: Hannan
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Howles
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Valerie N
authors.initials: VN
authors.lastname: Babinsky
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sian E
authors.initials: SE
authors.lastname: Piret
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Angela
authors.initials: A
authors.lastname: Rogers
authors.affiliation: ARUK Centre for Osteoarthritis Pathogenesis, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Freidin
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Stewart
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Anju
authors.initials: A
authors.lastname: Paudyal
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Tertius A
authors.initials: TA
authors.lastname: Hough
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.|Biomedical Sciences Research Institute, Ulster University, Coleraine, United Kingdom.
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Nesbit
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.affiliation: ARUK Centre for Osteoarthritis Pathogenesis, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
authors.forename: Tonia L
authors.initials: TL
authors.lastname: Vincent
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Stephen Dm
authors.initials: SD
authors.lastname: Brown
authors.affiliation: Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cox
authors.affiliation: Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; 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; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D009281:Naphthalenes / Q000008:administration & dosage* / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000097:blood; 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; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D002118:Calcium