{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T15:10:12Z","timestamp":1759072212442,"version":"3.44.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"10","funder":[{"name":"Intramural Research Program of the NIH: National Institute of Diabetes and Digestive and Kidney Diseases","award":["1ZIADK043006","1ZIADK075035"],"award-info":[{"award-number":["1ZIADK043006","1ZIADK075035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Glial cells missing 2 (GCM2) is an essential transcription factor for the development of parathyroid glands. Germline GCM2 variants that repress or enhance transcriptional activity predispose a subset of patients to hypoparathyroidism or hyperparathyroidism, respectively. A recurrent germline heterozygous activating missense variant of GCM2, p.Y394S has been identified in some patients with primary hyperparathyroidism. A genetically engineered knock-in mouse model of this variant corresponding to p.Y392S in the mouse Gcm2 gene (Gcm2+\/Y392S) did not show obvious parathyroid tumors. However, in GCM2-binding site mediated luciferase reporter assays in HEK293 cells, the mouse and the human variant both exhibited enhanced transcriptional activity. Therefore, we assessed the effect of this variant on gene expression in vivo in parathyroid glands from Gcm2+\/Y392S and WT mice. Using the 10x Genomics Visium platform, spatially resolved transcriptomic analysis was performed on formalin-fixed and paraffin-embedded (FFPE) tracheal tissue sections of Gcm2+\/Y392S and WT mice to capture RNA from parathyroid glands together with other cell types in the tissue sections. Transcriptome sequence data analysis detected 8 different clusters in the tissue sections based on similarity of gene expression profiles. Cluster-1, which contained parathyroid gland cells expressing Pth and Gcm2, was further evaluated for transcripts that were differentially expressed more than 2-fold in Gcm2+\/Y392S compared to WT. Increased transcript level of Lgals3 (galectin-3) was seen in Gcm2+\/Y392S parathyroid gland cells which is among markers of parathyroid carcinoma. Galectin-3 protein was detected in available FFPE human parathyroid samples of patients with germline heterozygous activating GCM2 variants, p.Y394S (n\u2009=\u20094\/10) or p.L379Q (n\u2009=\u20092\/2). These results indicate a potential for growth and malignancy of parathyroid glands expressing GCM2 variants. The transcriptomic data of mouse parathyroid gland cells generated in this study can serve as a valuable resource for investigating genes and pathways in normal or abnormal parathyroid gland growth and physiology.<\/jats:p>","DOI":"10.1093\/jbmrpl\/ziaf147","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T13:56:17Z","timestamp":1757426177000},"source":"Crossref","is-referenced-by-count":0,"title":["Spatial transcriptomic analysis of mouse parathyroid gland cells expressing an activating variant of <i>Gcm2<\/i>"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7533-0782","authenticated-orcid":false,"given":"Priyanka","family":"Bolel","sequence":"first","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremie Oliver","family":"Pi\u00f1a","sequence":"additional","affiliation":[{"name":"Section on Craniofacial Genetic Disorders, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]},{"name":"Department of Biomedical Engineering, University of Utah , Salt Lake City, UT, 84112 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7959-9842","authenticated-orcid":false,"given":"Fabio R","family":"Faucz","sequence":"additional","affiliation":[{"name":"Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]},{"name":"Hospital for Endocrine Surgery Research Center, HCA Research Institute , Tampa, FL, 33615 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R","family":"Iben","sequence":"additional","affiliation":[{"name":"Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wafa","family":"Abbas","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9201-3340","authenticated-orcid":false,"given":"Smita","family":"Jha","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William F","family":"Simonds","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1899-5152","authenticated-orcid":false,"given":"Lee S","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7557-3191","authenticated-orcid":false,"given":"Sunita K","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, 20892 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,9]]},"reference":[{"issue":"6792","key":"2025092810414782000_ref1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/35018111","article-title":"Genetic ablation of parathyroid glands reveals another source of parathyroid hormone","volume":"406","author":"Gunther","year":"2000","journal-title":"Nature"},{"issue":"1","key":"2025092810414782000_ref2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.ydbio.2007.02.014","article-title":"Gcm2 is required for the differentiation and survival of parathyroid precursor cells in the parathyroid\/thymus primordia","volume":"305","author":"Liu","year":"2007","journal-title":"Dev Biol"},{"issue":"1","key":"2025092810414782000_ref3","doi-asserted-by":"crossref","first-page":"e0210662","DOI":"10.1371\/journal.pone.0210662","article-title":"Gcm2 regulates the maintenance of parathyroid cells in adult mice","volume":"14","author":"Yamada","year":"2019","journal-title":"PLoS One"},{"key":"2025092810414782000_ref4","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/B978-0-12-397166-1.00006-0","volume-title":"The Parathyroids","author":"Brown","year":"2015","edition":"Third"},{"issue":"5","key":"2025092810414782000_ref5","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1210\/endrev\/bnad009","article-title":"Molecular and clinical spectrum of primary hyperparathyroidism","volume":"44","author":"Jha","year":"2023","journal-title":"Endocr Rev"},{"issue":"8","key":"2025092810414782000_ref6","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1172\/JCI200113180","article-title":"Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB","volume":"108","author":"Ding","year":"2001","journal-title":"J Clin Invest"},{"issue":"5","key":"2025092810414782000_ref7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1136\/jmg.2004.026898","article-title":"Identification of a novel mutation disrupting the DNA binding activity of GCM2 in autosomal recessive familial isolated hypoparathyroidism","volume":"42","author":"Baumber","year":"2005","journal-title":"J Med Genet"},{"issue":"5","key":"2025092810414782000_ref8","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1210\/jc.2004-2450","article-title":"GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone","volume":"90","author":"Thomee","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"issue":"9","key":"2025092810414782000_ref9","doi-asserted-by":"crossref","first-page":"3568","DOI":"10.1210\/jc.2007-2167","article-title":"Dominant-negative GCMB mutations cause an autosomal dominant form of hypoparathyroidism","volume":"93","author":"Mannstadt","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2025092810414782000_ref10","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1210\/jc.2007-1783","article-title":"Analysis of the GCM2 gene in isolated hypoparathyroidism: a molecular and biochemical study","volume":"93","author":"Maret","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2025092810414782000_ref11","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1093\/hmg\/ddq084","article-title":"Identification and characterization of novel parathyroid-specific transcription factor glial cells missing homolog B (GCMB) mutations in eight families with autosomal recessive hypoparathyroidism","volume":"19","author":"Bowl","year":"2010","journal-title":"Hum Mol Genet"},{"issue":"3","key":"2025092810414782000_ref12","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1530\/EJE-21-0433","article-title":"Novel glial cells Missing-2 (GCM2) variants in parathyroid disorders","volume":"186","author":"Canaff","year":"2022","journal-title":"Eur J Endocrinol"},{"issue":"1","key":"2025092810414782000_ref13","doi-asserted-by":"crossref","first-page":"bvac166","DOI":"10.1210\/jendso\/bvac166","article-title":"Glial cell missing homolog 2 mutation causing severe hypoparathyroidism: report of two cases with novel mutations","volume":"7","author":"Singhania","year":"2022","journal-title":"J Endocr Soc"},{"issue":"5","key":"2025092810414782000_ref14","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1016\/j.ajhg.2016.08.018","article-title":"GCM2-activating mutations in familial isolated hyperparathyroidism","volume":"99","author":"Guan","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"5","key":"2025092810414782000_ref15","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1210\/js.2017-00043","article-title":"Ethnicity of patients with germline GCM2-activating variants and primary hyperparathyroidism","volume":"1","author":"Guan","year":"2017","journal-title":"J Endocr Soc"},{"issue":"6","key":"2025092810414782000_ref16","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1210\/jc.2018-02517","article-title":"Analysis of activating GCM2 sequence variants in sporadic parathyroid adenomas","volume":"104","author":"Riccardi","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2025092810414782000_ref17","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s40618-019-01107-5","article-title":"Whole exome sequencing in familial isolated primary hyperparathyroidism","volume":"43","author":"Cetani","year":"2020","journal-title":"J Endocrinol Investig"},{"issue":"1","key":"2025092810414782000_ref18","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1530\/EJE-19-0641","article-title":"Should the GCM2 gene be tested when screening for familial primary hyperparathyroidism?","volume":"182","author":"Coppin","year":"2020","journal-title":"Eur J Endocrinol"},{"issue":"10","key":"2025092810414782000_ref19","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.4158\/EP-2020-0132","article-title":"Germline GCM2 mutation screening in Chinese primary hyperparathyroidism patients","volume":"26","author":"Song","year":"2020","journal-title":"Endocr Pract"},{"issue":"1","key":"2025092810414782000_ref20","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1038\/s41598-021-82661-y","article-title":"Five patients with disorders of calcium metabolism presented with GCM2 gene variants","volume":"11","author":"Garcia-Castano","year":"2021","journal-title":"Sci Rep"},{"key":"2025092810414782000_ref21","doi-asserted-by":"crossref","first-page":"853171","DOI":"10.3389\/fendo.2022.853171","article-title":"Germline mutations related to primary hyperparathyroidism identified by next-generation sequencing","volume":"13","author":"Park","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"5","key":"2025092810414782000_ref22","doi-asserted-by":"crossref","first-page":"e2021","DOI":"10.1210\/clinem\/dgab929","article-title":"GCM2 variants in familial and multiglandular primary hyperparathyroidism","volume":"107","author":"Vincze","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"2025092810414782000_ref23","doi-asserted-by":"crossref","first-page":"bvad086","DOI":"10.1210\/jendso\/bvad086","article-title":"Variant Tyr 394Ser in the GCM2 gene is rare in a cohort of Ashkenazi Jews with primary hyperparathyroidism","volume":"7","author":"Tolkin","year":"2023","journal-title":"J Endocr Soc"},{"key":"2025092810414782000_ref24","doi-asserted-by":"crossref","first-page":"1254156","DOI":"10.3389\/fendo.2023.1254156","article-title":"GCM2 p.Tyr394Ser variant in Ashkenazi Israeli patients with suspected familial isolated hyperparathyroidism","volume":"14","author":"Szalat","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2025092810414782000_ref25","article-title":"Germline mutations of GCM2 cause a novel variant of hereditary primary hyperparathyroidism","volume":"77","author":"Iacobone","year":"2025","journal-title":"Updat Surg"},{"issue":"4","key":"2025092810414782000_ref26","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1007\/s11248-014-9799-7","article-title":"Generation of mice encoding a conditional null allele of Gcm2","volume":"23","author":"Yuan","year":"2014","journal-title":"Transgenic Res"},{"issue":"11","key":"2025092810414782000_ref27","doi-asserted-by":"crossref","first-page":"bvad126","DOI":"10.1210\/jendso\/bvad126","article-title":"A knock-in mouse model of the Gcm2 variant p.Y392S develops normal parathyroid glands","volume":"7","author":"Parekh","year":"2023","journal-title":"J Endocr Soc"},{"issue":"10","key":"2025092810414782000_ref28","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1210\/clinem\/dgad136","article-title":"Germline- and somatic-inactivating FLCN variants in parathyroid cancer and atypical parathyroid tumors","volume":"108","author":"Jha","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2025092810414782000_ref29","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1038\/s41467-024-46181-3","article-title":"Epigenetic profiling reveals key genes and cis-regulatory networks specific to human parathyroids","volume":"15","author":"Jung","year":"2024","journal-title":"Nat Commun"},{"issue":"8","key":"2025092810414782000_ref30","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1016\/j.humpath.2005.06.020","article-title":"Galectin-3 expression in parathyroid carcinoma: immunohistochemical study of 26 cases","volume":"36","author":"Bergero","year":"2005","journal-title":"Hum Pathol"},{"issue":"2","key":"2025092810414782000_ref31","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/cncr.24037","article-title":"Defining a molecular phenotype for benign and malignant parathyroid tumors","volume":"115","author":"Fernandez-Ranvier","year":"2009","journal-title":"Cancer"},{"issue":"11","key":"2025092810414782000_ref32","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1007\/s00268-014-2700-2","article-title":"Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an immunohistochemical panel to aid in the diagnosis of parathyroid cancer","volume":"38","author":"Truran","year":"2014","journal-title":"World J Surg"},{"issue":"6","key":"2025092810414782000_ref33","doi-asserted-by":"crossref","first-page":"421","DOI":"10.5001\/omj.2015.84","article-title":"The role of parafibromin, galectin-3, HBME-1, and Ki-67 in the differential diagnosis of parathyroid tumors","volume":"30","author":"Karaarslan","year":"2015","journal-title":"Oman Med J"},{"issue":"4","key":"2025092810414782000_ref34","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s12022-019-09592-3","article-title":"Using a novel diagnostic nomogram to differentiate malignant from benign parathyroid neoplasms","volume":"30","author":"Silva-Figueroa","year":"2019","journal-title":"Endocr Pathol"},{"key":"2025092810414782000_ref35","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/j.1749-6632.2011.06221.x","article-title":"Transcription factors in parathyroid development: lessons from hypoparathyroid disorders","volume":"1237(2011)","author":"Grigorieva","year":"2011","journal-title":"Ann N Y Acad Sci"},{"issue":"6294","key":"2025092810414782000_ref36","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and analysis of gene expression in tissue sections by spatial transcriptomics","volume":"353","author":"Stahl","year":"2016","journal-title":"Science."},{"issue":"1","key":"2025092810414782000_ref37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12964-023-01225-x","article-title":"PI3K\/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells","volume":"21","author":"Maharati","year":"2023","journal-title":"Cell Commun Signal"},{"issue":"7","key":"2025092810414782000_ref38","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1158\/1541-7786.MCR-15-0068","article-title":"Dissecting the dual role of AMPK in cancer: from experimental to human studies","volume":"13","author":"Zadra","year":"2015","journal-title":"Mol Cancer Res"},{"issue":"5","key":"2025092810414782000_ref39","doi-asserted-by":"crossref","first-page":"2115","DOI":"10.1158\/0008-5472.CAN-09-2979","article-title":"Loss of FOXA1\/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer","volume":"70","author":"Song","year":"2010","journal-title":"Cancer Res"},{"issue":"12","key":"2025092810414782000_ref40","doi-asserted-by":"crossref","DOI":"10.1172\/JCI157574","article-title":"FOXA2 suppresses endometrial carcinogenesis and epithelial-mesenchymal transition by regulating enhancer activity","volume":"132","author":"Sahoo","year":"2022","journal-title":"J Clin Invest"},{"issue":"1","key":"2025092810414782000_ref41","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1007\/s12022-022-09709-1","article-title":"Overview of the 2022 WHO classification of parathyroid tumors","volume":"33","author":"Erickson","year":"2022","journal-title":"Endocr Pathol"},{"issue":"1","key":"2025092810414782000_ref42","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.surg.2017.04.027","article-title":"Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure","volume":"163","author":"El Lakis","year":"2018","journal-title":"Surgery"}],"container-title":["JBMR Plus"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jbmrplus\/advance-article-pdf\/doi\/10.1093\/jbmrpl\/ziaf147\/64230350\/ziaf147.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/10\/ziaf147\/64230350\/ziaf147.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article-pdf\/9\/10\/ziaf147\/64230350\/ziaf147.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T14:41:56Z","timestamp":1759070516000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jbmrplus\/article\/doi\/10.1093\/jbmrpl\/ziaf147\/8249906"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,3]]},"references-count":42,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,9,3]]}},"URL":"https:\/\/doi.org\/10.1093\/jbmrpl\/ziaf147","relation":{},"ISSN":["2473-4039"],"issn-type":[{"type":"electronic","value":"2473-4039"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,3]]},"article-number":"ziaf147"}}