{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T13:32:28Z","timestamp":1791639148031,"version":"4.3.4"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:sec>\n<jats:title>Objective<\/jats:title>\n<jats:p>The aim of this study was to analyze variants of the gene glial cells missing-2 (<jats:italic>GCM2<\/jats:italic>), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Design<\/jats:title>\n<jats:p>We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of <jats:italic>GCM2<\/jats:italic> variants.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for <jats:italic>CASR, PTH, GNA11<\/jats:italic> and <jats:italic>GCM2<\/jats:italic> mutations. DNA of hyperparathyroid individuals underwent<jats:italic> MEN1, CDKN1B, CDC73,<\/jats:italic>\n<jats:italic>CASR<\/jats:italic>, <jats:italic>RET<\/jats:italic> and <jats:italic>GCM2<\/jats:italic> sequencing. The actions of identified<jats:italic> GCM2<\/jats:italic> variants were evaluated by <jats:italic>in vitro<\/jats:italic> functional analyses.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>A novel homozygous p.R67C <jats:italic>GCM2<\/jats:italic> mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and <jats:italic>in silico<\/jats:italic> structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous <jats:italic>GCM2<\/jats:italic> variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced <jats:italic>in vitro<\/jats:italic>transcriptional activity, including increased stimulation of the PTH promoter.<\/jats:p>\n<\/jats:sec>\n<jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>We provide evidence that two novel <jats:italic>GCM2<\/jats:italic> R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter <jats:italic>in vitro<\/jats:italic> and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1530\/eje-21-0433","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T19:13:01Z","timestamp":1642446781000},"page":"351-366","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-7","source":"Crossref","is-referenced-by-count":25,"title":["Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders"],"prefix":"10.1093","volume":"186","author":[{"given":"Lucie","family":"Canaff","sequence":"first","affiliation":[{"name":"1Metabolic Complications and Disorders, Research Institute-McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Guarnieri","sequence":"additional","affiliation":[{"name":"2Division of Medical Genetics and Unit of Endocrinology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoojung","family":"Kim","sequence":"additional","affiliation":[{"name":"1Metabolic Complications and Disorders, Research Institute-McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty Y L","family":"Wong","sequence":"additional","affiliation":[{"name":"3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-2508","authenticated-orcid":true,"given":"Alexis","family":"Nolin-Lapalme","sequence":"additional","affiliation":[{"name":"1Metabolic Complications and Disorders, Research Institute-McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E C","family":"Cole","sequence":"additional","affiliation":[{"name":"3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6525-0439","authenticated-orcid":true,"given":"Salvatore","family":"Minisola","sequence":"additional","affiliation":[{"name":"4Department of Internal Medicine and Medical Disciplines, \u2018Sapienza\u2019 Rome University, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Eller-Vainicher","sequence":"additional","affiliation":[{"name":"5Department of Medical Sciences and Community, Fondazione Ca\u2019Granda IRCCS Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Cetani","sequence":"additional","affiliation":[{"name":"6University Hospital of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Repaci","sequence":"additional","affiliation":[{"name":"7Unit of Endocrinology, S. Orsola Malpighi Hospital, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Turchetti","sequence":"additional","affiliation":[{"name":"8Center for the Studies of Hereditary Cancers, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8140-3175","authenticated-orcid":true,"given":"Sabrina","family":"Corbetta","sequence":"additional","affiliation":[{"name":"9Endocrinology and Diabetology Service, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy"},{"name":"10Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Scillitani","sequence":"additional","affiliation":[{"name":"2Division of Medical Genetics and Unit of Endocrinology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Goltzman","sequence":"additional","affiliation":[{"name":"1Metabolic Complications and Disorders, Research Institute-McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","container-title":["European Journal of Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/eje.bioscientifica.com\/view\/journals\/eje\/186\/3\/EJE-21-0433.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/eje.bioscientifica.com\/downloadpdf\/journals\/eje\/186\/3\/EJE-21-0433.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T16:16:45Z","timestamp":1676391405000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ejendo\/article\/186\/3\/351\/6954326"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":0,"journal-issue":{"issue":"3"},"URL":"https:\/\/doi.org\/10.1530\/eje-21-0433","relation":{},"ISSN":["0804-4643","1479-683X"],"issn-type":[{"value":"0804-4643","type":"print"},{"value":"1479-683X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,1]]}}}