{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T21:08:27Z","timestamp":1774645707422,"version":"3.50.1"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,2,10]],"date-time":"2024-02-10T00:00:00Z","timestamp":1707523200000},"content-version":"vor","delay-in-days":2935,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008392","name":"Medical Sciences, Danish Council for Independent Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germline gain-of-function mutations of G-protein subunit \u03b1-11 (G\u03b111). To date G\u03b111 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met G\u03b111 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three-dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal \u03b15 helix, which may affect G-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant (Met340) G\u03b111 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 G\u03b111 led to a leftward shift of the concentration-response curve with a significantly (p\u2009&amp;lt;\u20090.0001) reduced mean half-maximal concentration (EC50) value of 2.44\u2009mM (95% CI, 2.31 to 2.77\u2009mM) when compared to the wild-type EC50 of 3.14\u2009mM (95% CI, 3.03 to 3.26\u2009mM), consistent with a gain-of-function mutation. A novel His403Gln variant in transforming growth factor, beta-induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain-of-function G\u03b111 mutation, Val340Met, causing ADH2 demonstrates the importance of the G\u03b111 C-terminal region for G-protein function and CaSR signal transduction. \u00a9 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.2797","type":"journal-article","created":{"date-parts":[[2016,1,28]],"date-time":"2016-01-28T09:12:52Z","timestamp":1453972372000},"page":"1207-1214","source":"Crossref","is-referenced-by-count":37,"title":["Identification of a G-Protein Subunit-\u03b111 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)"],"prefix":"10.1093","volume":"31","author":[{"given":"Sian E","family":"Piret","sequence":"first","affiliation":[{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline M","family":"Gorvin","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alistair T","family":"Pagnamenta","sequence":"additional","affiliation":[{"name":"Oxford NIHR Comprehensive Biomedical Research CentreOxfordUK"},{"name":"Wellcome Trust Centre for Human GeneticsRoosevelt DriveOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A","family":"Howles","sequence":"additional","affiliation":[{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Treena","family":"Cranston","sequence":"additional","affiliation":[{"name":"Oxford University Hospitals NHS TrustOxford Medical Genetics LaboratoriesChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nigel","family":"Rust","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of PathologyUniversity of OxfordSouth Parks RoadOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M Andrew","family":"Nesbit","sequence":"additional","affiliation":[{"name":"Biomedical Sciences Research InstituteUlster UniversityColeraineUK"},{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Glaser","sequence":"additional","affiliation":[{"name":"Department of Internal MedicineHadassah-Hebrew University Medical CenterJerusalemIsrael"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenny C","family":"Taylor","sequence":"additional","affiliation":[{"name":"Oxford NIHR Comprehensive Biomedical Research CentreOxfordUK"},{"name":"Wellcome Trust Centre for Human GeneticsRoosevelt DriveOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas E","family":"Buchs","sequence":"additional","affiliation":[{"name":"Department of Medicine DAssaf Harofe Medical CenterZerifinIsrael"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fadil M","family":"Hannan","sequence":"additional","affiliation":[{"name":"Department of Musculoskeletal BiologyInstitute of Ageing and Chronic DiseaseUniversity of LiverpoolLiverpoolUK"},{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajesh V","family":"Thakker","sequence":"additional","affiliation":[{"name":"Oxford NIHR Comprehensive Biomedical Research CentreOxfordUK"},{"name":"Academic Endocrine Unit, University of Oxford, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,1,28]]},"reference":[{"issue":"15","key":"2024021014183223600_jbmr2797-bib-0001","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1056\/NEJM199610103351505","article-title":"A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor","volume":"335","author":"Pearce","year":"1996","journal-title":"N Engl J Med"},{"issue":"12","key":"2024021014183223600_jbmr2797-bib-0002","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1093\/hmg\/dds105","article-title":"Identification of 70 calcium-sensing receptor mutations in hyper- and hypo-calcaemic patients: evidence for clustering of extracellular domain mutations at calcium-binding sites","volume":"21","author":"Hannan","year":"2012","journal-title":"Hum Mol Genet"},{"issue":"26","key":"2024021014183223600_jbmr2797-bib-0003","doi-asserted-by":"crossref","first-page":"2476","DOI":"10.1056\/NEJMoa1300253","article-title":"Mutations affecting G-protein subunit alpha11 in hypercalcemia and hypocalcemia","volume":"368","author":"Nesbit","year":"2013","journal-title":"N Engl J Med"},{"issue":"7","key":"2024021014183223600_jbmr2797-bib-0004","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrm1154","article-title":"Extracellular calcium sensing and signalling","volume":"4","author":"Hofer","year":"2003","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"3","key":"2024021014183223600_jbmr2797-bib-0005","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.beem.2013.04.007","article-title":"Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism","volume":"27","author":"Hannan","year":"2013","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"issue":"26","key":"2024021014183223600_jbmr2797-bib-0006","doi-asserted-by":"crossref","first-page":"2532","DOI":"10.1056\/NEJMc1300278","article-title":"Germline mutations affecting Galpha11 in hypoparathyroidism","volume":"368","author":"Mannstadt","year":"2013","journal-title":"N Engl J Med"},{"issue":"9","key":"2024021014183223600_jbmr2797-bib-0007","doi-asserted-by":"crossref","first-page":"E1774","DOI":"10.1210\/jc.2014-1029","article-title":"Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization","volume":"99","author":"Li","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2024021014183223600_jbmr2797-bib-0008","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1111\/j.1365-2265.2011.04142.x","article-title":"Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia \u2212 a German survey","volume":"75","author":"Raue","year":"2011","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"12","key":"2024021014183223600_jbmr2797-bib-0009","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.1210\/jcem.85.12.7035","article-title":"Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor: is it possible to differentiate the two disorders","volume":"85","author":"Yamamoto","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"issue":"37","key":"2024021014183223600_jbmr2797-bib-0010","doi-asserted-by":"crossref","first-page":"13566","DOI":"10.1073\/pnas.0405516101","article-title":"Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification","volume":"101","author":"Hough","year":"2004","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"2024021014183223600_jbmr2797-bib-0011","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1097\/01.ASN.0000025781.16723.68","article-title":"Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome","volume":"13","author":"Vargas-Poussou","year":"2002","journal-title":"J Am Soc Nephrol"},{"issue":"9334","key":"2024021014183223600_jbmr2797-bib-0012","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/S0140-6736(02)09842-2","article-title":"Association between activating mutations of calcium-sensing receptor and Bartter's syndrome","volume":"360","author":"Watanabe","year":"2002","journal-title":"Lancet"},{"issue":"4","key":"2024021014183223600_jbmr2797-bib-0013","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1152\/physrev.00003.2005","article-title":"Mammalian G proteins and their cell type specific functions","volume":"85","author":"Wettschureck","year":"2005","journal-title":"Physiol Rev"},{"key":"2024021014183223600_jbmr2797-bib-0014","first-page":"2019","article-title":"current perspectives","volume":"7","author":"Vazirani","year":"2013","journal-title":"Clin Ophthalmol"},{"issue":"7","key":"2024021014183223600_jbmr2797-bib-0015","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/ng.3304","article-title":"Factors influencing success of clinical genome sequencing across a broad spectrum of disorders","volume":"47","author":"Taylor","year":"2015","journal-title":"Nat Genet"},{"issue":"7","key":"2024021014183223600_jbmr2797-bib-0016","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1101\/gr.080531.108","article-title":"The consensus coding sequence (CCDS) project: identifying a common protein-coding gene set for the human and mouse genomes","volume":"19","author":"Pruitt","year":"2009","journal-title":"Genome Res"},{"issue":"6","key":"2024021014183223600_jbmr2797-bib-0017","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1101\/gr.111120.110","article-title":"a statistical algorithm for sensitive and fast mapping of Illumina sequence reads","volume":"21","author":"Lunter","year":"2011","journal-title":"Genome Res"},{"issue":"8","key":"2024021014183223600_jbmr2797-bib-0018","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/ng.3036","article-title":"Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications","volume":"46","author":"Rimmer","year":"2014","journal-title":"Nat Genet"},{"issue":"21","key":"2024021014183223600_jbmr2797-bib-0019","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1056\/NEJMoa1307557","article-title":"Mutant prolactin receptor and familial hyperprolactinemia","volume":"369","author":"Newey","year":"2013","journal-title":"N Engl J Med"},{"issue":"6006","key":"2024021014183223600_jbmr2797-bib-0020","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1126\/science.1193438","article-title":"Kinetic scaffolding mediated by a phospholipase C-beta and Gq signaling complex","volume":"330","author":"Waldo","year":"2010","journal-title":"Science"},{"issue":"1","key":"2024021014183223600_jbmr2797-bib-0021","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/ng.2492","article-title":"Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 3","volume":"45","author":"Nesbit","year":"2013","journal-title":"Nat Genet"},{"issue":"18","key":"2024021014183223600_jbmr2797-bib-0022","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1093\/hmg\/ddv226","article-title":"Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects","volume":"24","author":"Hannan","year":"2015","journal-title":"Hum Mol Genet"},{"issue":"7564","key":"2024021014183223600_jbmr2797-bib-0023","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/nature14663","article-title":"Universal allosteric mechanism for Galpha activation by GPCRs","volume":"524","author":"Flock","year":"2015","journal-title":"Nature"},{"issue":"7366","key":"2024021014183223600_jbmr2797-bib-0024","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure of the beta2 adrenergic receptor-Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature"},{"issue":"9","key":"2024021014183223600_jbmr2797-bib-0025","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nsmb.3070","article-title":"Probing Galphai1 protein activation at single-amino acid resolution","volume":"22","author":"Sun","year":"2015","journal-title":"Nat Struct Mol Biol"},{"issue":"35","key":"2024021014183223600_jbmr2797-bib-0026","doi-asserted-by":"crossref","first-page":"24475","DOI":"10.1074\/jbc.M114.572875","article-title":"Hamm HE A conserved phenylalanine as a relay between the alpha5 helix and the GDP binding region of heterotrimeric Gi protein alpha subunit","volume":"289","author":"Kaya","year":"2014","journal-title":"J Biol Chem"},{"issue":"23","key":"2024021014183223600_jbmr2797-bib-0027","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1056\/NEJMoa1000584","article-title":"Mutations in GNA11 in uveal melanoma","volume":"363","author":"Van Raamsdonk","year":"2010","journal-title":"N Engl J Med"},{"issue":"1","key":"2024021014183223600_jbmr2797-bib-0028","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.gene.2012.04.061","article-title":"The point mutation and polymorphism in keratoconus candidate gene TGFBI in Chinese population","volume":"503","author":"Guan","year":"2012","journal-title":"Gene"},{"issue":"2","key":"2024021014183223600_jbmr2797-bib-0029","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1002\/(SICI)1098-1004(1999)14:2<126::AID-HUMU4>3.0.CO;2-W","article-title":"Heterogeneity in granular corneal dystrophy: identification of three causative mutations in the TGFBI (BIGH3) gene-lessons for corneal amyloidogenesis","volume":"14","author":"Stewart","year":"1999","journal-title":"Hum Mutat"},{"issue":"9","key":"2024021014183223600_jbmr2797-bib-0030","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1210\/en.2015-1269","article-title":"The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing receptor (CaSR) mutation: relevance to autosomal dominant hypocalcemia type 1 (ADH1)","volume":"156","author":"Hannan","year":"2015","journal-title":"Endocrinology"}],"container-title":["Journal of Bone and Mineral Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjbmr.2797","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbmr.2797","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jbmr.2797","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/6\/1207\/56649206\/jbmr2797.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmr\/article-pdf\/31\/6\/1207\/56649206\/jbmr2797.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T14:55:51Z","timestamp":1710341751000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmr\/article\/31\/6\/1207-1214\/7605151"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,28]]},"references-count":30,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,1,28]]},"published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.1002\/jbmr.2797","relation":{},"ISSN":["0884-0431","1523-4681"],"issn-type":[{"value":"0884-0431","type":"print"},{"value":"1523-4681","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6,1]]},"published":{"date-parts":[[2016,1,28]]}}}