{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T10:44:40Z","timestamp":1788864280110,"version":"build-2803163510"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2017,2,9]],"date-time":"2017-02-09T00:00:00Z","timestamp":1486598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,2,9]]},"abstract":"<jats:p>\n                    Heterozygous germline gain-of-function mutations of G-protein subunit \u03b1\n                    <jats:sub>11<\/jats:sub>\n                    (G\u03b1\n                    <jats:sub>11<\/jats:sub>\n                    ), 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 (\n                    <jats:italic>Dsk7<\/jats:italic>\n                    ) \u2014 which has a germline hypermorphic G\u03b1\n                    <jats:sub>11<\/jats:sub>\n                    mutation, Ile62Val \u2014 may be a model for ADH2 and allow evaluation of calcilytics, which are CaSR negative allosteric modulators, as a targeted therapy for this disorder. Mutant\n                    <jats:italic>Dsk7\/+<\/jats:italic>\n                    and\n                    <jats:italic>Dsk7\/Dsk7<\/jats:italic>\n                    mice were shown to have hypocalcemia and reduced plasma PTH concentrations, similar to ADH2 patients. In vitro studies showed the mutant Val62 G\u03b1\n                    <jats:sub>11<\/jats:sub>\n                    to 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 in\n                    <jats:italic>Dsk7\/Dsk7<\/jats:italic>\n                    and\n                    <jats:italic>Dsk7\/+<\/jats:italic>\n                    mice, which became normocalcemic. Thus, these studies have established\n                    <jats:italic>Dsk7<\/jats:italic>\n                    mice, which harbor a germline gain-of-function G\u03b1\n                    <jats:sub>11<\/jats:sub>\n                    mutation, as a model for ADH2 and have demonstrated calcilytics as a potential targeted therapy.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.91103","type":"journal-article","created":{"date-parts":[[2017,2,8]],"date-time":"2017-02-08T11:00:49Z","timestamp":1486551649000},"source":"Crossref","is-referenced-by-count":33,"title":["G\u03b111 mutation in mice causes hypocalcemia rectifiable by calcilytic therapy"],"prefix":"10.1172","volume":"2","author":[{"given":"Caroline M.","family":"Gorvin","sequence":"first","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadil M.","family":"Hannan","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."},{"name":"Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A.","family":"Howles","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie N.","family":"Babinsky","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian E.","family":"Piret","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Rogers","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Freidin","sequence":"additional","affiliation":[{"name":"ARUK Centre for Osteoarthritis Pathogenesis, The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6787-5288","authenticated-orcid":true,"given":"Michelle","family":"Stewart","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anju","family":"Paudyal","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tertius A.","family":"Hough","sequence":"additional","affiliation":[{"name":"Medical Research Council (MRC) Mammalian Genetics Unit and Mary Lyon Centre, MRC Harwell Institute, Harwell Science and Innovation Campus, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7222-4124","authenticated-orcid":true,"given":"M. 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