{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:39:04Z","timestamp":1792723144087,"version":"4.5.0"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":87,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Research Foundation of Korea","award":["NRF-2021R1G1A1092117"],"award-info":[{"award-number":["NRF-2021R1G1A1092117"]}]},{"name":"Handok Pharmaceutical Inc"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pseudohypoparathyroidism (PHP) is a heterogeneous disorder caused by genetic or epigenetic changes at the\n                      <jats:italic>GNAS<\/jats:italic>\n                      locus on chromosome 20q13.3 leading to impaired cyclic adenosine monophosphate (cAMP)-dependent signaling pathway via the alpha-subunit of the stimulatory G protein (G\n                      <jats:sub>s<\/jats:sub>\n                      \u03b1). Unlike PHP type 1\u00a0A (PHP1A), which occurs due to\n                      <jats:italic>GNAS<\/jats:italic>\n                      variant and low G\n                      <jats:sub>s<\/jats:sub>\n                      \u03b1 activity, the activity of G\n                      <jats:sub>s<\/jats:sub>\n                      \u03b1 is normal in PHP type 1\u00a0C (PHP1C) despite the same phenotypic characteristics as PHP1A. However, the genetic cause of PHP1C is unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The likely causative variant of PHP1C was investigated using next-generation sequencing, and G\n                      <jats:sub>s<\/jats:sub>\n                      \u03b1 protein levels and function were assessed in patient-derived cells by immunoblotting, immunocytochemistry and cAMP measurement.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a\n                      <jats:italic>de novo<\/jats:italic>\n                      genomic deletion in a promoter region and 5\u2019 untranslated region (UTR) of\n                      <jats:italic>GNAS (<\/jats:italic>\n                      5\u2019 deletion of\n                      <jats:italic>GNAS)<\/jats:italic>\n                      , in a participant with PHP1C. Furthermore, although the mRNA and protein levels of\n                      <jats:italic>GNAS<\/jats:italic>\n                      were maintained, cAMP production was impaired in PHP1C, implicating a functional abnormality rather than quantitative changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This novel 5\u2019-UTR deletion of\n                      <jats:italic>GNAS<\/jats:italic>\n                      may underlie PHP1C and highlights the importance of assessing non-coding regions of GNAS in participants with PHP1C or PHP1A who lack pathogenic variants in conventional genetic tests.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-026-02439-x","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T12:18:01Z","timestamp":1785241081000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic evidence linking the promoter region and 5\u2019-UTR deletion of GNAS with pseudohypoparathyroidism type 1\u00a0C"],"prefix":"10.1186","volume":"19","author":[{"given":"Chung","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Ji","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Chul","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saeyoung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Yeon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Seok","family":"Ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woong-Yang","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Yoon","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"2439_CR1","doi-asserted-by":"publisher","unstructured":"Weinstein LS. Albright Hereditary Osteodystrophy, Pseudohypoparathyroidism, and Gs Deficiency. In: G Proteins, Receptors, and Disease. Edited by Spiegel AM. Totowa: Humana Press; 1998:23\u201356. https:\/\/doi.org\/10.1007\/978-1-4612-1802-9_2.","DOI":"10.1007\/978-1-4612-1802-9_2"},{"issue":"6","key":"2439_CR2","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1002\/humu.21489","volume":"32","author":"S Thiele","year":"2011","unstructured":"Thiele S, de Sanctis L, Werner R, Grotzinger J, Aydin C, Juppner H, Bastepe M, Hiort O. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsalpha-receptor interaction. Hum Mutat. 2011;32(6):653\u201360.","journal-title":"Hum Mutat"},{"issue":"1","key":"2439_CR3","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1210\/jcem.87.1.8133","volume":"87","author":"A Linglart","year":"2002","unstructured":"Linglart A, Carel JC, Garabedian M, Le T, Mallet E, Kottler ML. GNAS1 lesions in pseudohypoparathyroidism Ia and Ic: genotype phenotype relationship and evidence of the maternal transmission of the hormonal resistance. J Clin Endocrinol Metab. 2002;87(1):189\u201397.","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2439_CR4","doi-asserted-by":"publisher","first-page":"E1564","DOI":"10.1210\/jc.2013-4477","volume":"99","author":"B Brix","year":"2014","unstructured":"Brix B, Werner R, Staedt P, Struve D, Hiort O, Thiele S. Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders. J Clin Endocrinol Metab. 2014;99(8):E1564\u20131570.","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2439_CR5","doi-asserted-by":"publisher","first-page":"P1","DOI":"10.1530\/EJE-16-0107","volume":"175","author":"S Thiele","year":"2016","unstructured":"Thiele S, Mantovani G, Barlier A, Boldrin V, Bordogna P, De Sanctis L, Elli FM, Freson K, Garin I, Grybek V, et al. From pseudohypoparathyroidism to inactivating PTH\/PTHrP signalling disorder (iPPSD), a novel classification proposed by the EuroPHP network. Eur J Endocrinol. 2016;175(6):P1\u201317.","journal-title":"Eur J Endocrinol"},{"issue":"6","key":"2439_CR6","doi-asserted-by":"publisher","first-page":"2370","DOI":"10.1210\/jc.2006-2287","volume":"92","author":"GP de Nanclares","year":"2007","unstructured":"de Nanclares GP, Fernandez-Rebollo E, Santin I, Garcia-Cuartero B, Gaztambide S, Menendez E, Morales MJ, Pombo M, Bilbao JR, Barros F, et al. Epigenetic defects of GNAS in patients with pseudohypoparathyroidism and mild features of Albright\u2019s hereditary osteodystrophy. J Clin Endocrinol Metab. 2007;92(6):2370\u20133.","journal-title":"J Clin Endocrinol Metab"},{"issue":"Suppl 2","key":"2439_CR7","first-page":"647","volume":"19","author":"W Ahrens","year":"2006","unstructured":"Ahrens W, Hiort O. Determination of Gs alpha protein activity in Albright\u2019s hereditary osteodystrophy. J Pediatr Endocrinol Metab. 2006;19(Suppl 2):647\u201351.","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"5","key":"2439_CR8","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","volume":"17","author":"S Richards","year":"2015","unstructured":"Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405\u201324.","journal-title":"Genet Med"},{"issue":"14","key":"2439_CR9","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754\u201360.","journal-title":"Bioinformatics"},{"issue":"16","key":"2439_CR10","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. Genome Project Data Processing S: The Sequence Alignment\/Map format and SAMtools. Bioinformatics. 2009;25(16):2078\u20139.","journal-title":"Bioinformatics"},{"issue":"9","key":"2439_CR11","doi-asserted-by":"publisher","first-page":"1297","DOI":"10.1101\/gr.107524.110","volume":"20","author":"A McKenna","year":"2010","unstructured":"McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297\u2013303.","journal-title":"Genome Res"},{"issue":"1","key":"2439_CR12","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, Batut P, Chaisson M, Gingeras TR. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15\u201321.","journal-title":"Bioinformatics"},{"issue":"1","key":"2439_CR13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nbt.1754","volume":"29","author":"JT Robinson","year":"2011","unstructured":"Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES, Getz G, Mesirov JP. Integrative genomics viewer. Nat Biotechnol. 2011;29(1):24\u20136.","journal-title":"Nat Biotechnol"},{"issue":"10","key":"2439_CR14","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1210\/jc.2011-1048","volume":"96","author":"G Mantovani","year":"2011","unstructured":"Mantovani G. Clinical review: Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab. 2011;96(10):3020\u201330.","journal-title":"J Clin Endocrinol Metab"},{"issue":"8","key":"2439_CR15","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1038\/s41574-018-0042-0","volume":"14","author":"G Mantovani","year":"2018","unstructured":"Mantovani G, Bastepe M, Monk D, de Sanctis L, Thiele S, Usardi A, Ahmed SF, Bufo R, Choplin T, De Filippo G, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat Rev Endocrinol. 2018;14(8):476\u2013500.","journal-title":"Nat Rev Endocrinol"},{"issue":"6","key":"2439_CR16","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1210\/clinem\/dgab060","volume":"106","author":"H Juppner","year":"2021","unstructured":"Juppner H. Molecular Definition of Pseudohypoparathyroidism Variants. J Clin Endocrinol Metab. 2021;106(6):1541\u201352.","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2439_CR17","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1677\/jme.0.0200163","volume":"20","author":"J Novotny","year":"1998","unstructured":"Novotny J, Svoboda P. The long (Gs(alpha)-L) and short (Gs(alpha)-S) variants of the stimulatory guanine nucleotide-binding protein. Do they behave in an identical way? J Mol Endocrinol. 1998;20(2):163\u201373.","journal-title":"J Mol Endocrinol"},{"issue":"12","key":"2439_CR18","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1038\/gim.2018.47","volume":"20","author":"J Leclerc","year":"2018","unstructured":"Leclerc J, Flament C, Lovecchio T, Delattre L, Ait Yahya E, Baert-Desurmont S, Burnichon N, Bronner M, Cabaret O, Lejeune S, et al. Diversity of genetic events associated with MLH1 promoter methylation in Lynch syndrome families with heritable constitutional epimutation. Genet Med. 2018;20(12):1589\u201399.","journal-title":"Genet Med"},{"issue":"10","key":"2439_CR19","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1002\/ijc.24230","volume":"124","author":"A Gylling","year":"2009","unstructured":"Gylling A, Ridanpaa M, Vierimaa O, Aittomaki K, Avela K, Kaariainen H, Laivuori H, Poyhonen M, Sallinen SL, Wallgren-Pettersson C, et al. Large genomic rearrangements and germline epimutations in Lynch syndrome. Int J Cancer. 2009;124(10):2333\u201340.","journal-title":"Int J Cancer"},{"issue":"3","key":"2439_CR20","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1038\/ejhg.2011.187","volume":"20","author":"SJ Kim","year":"2012","unstructured":"Kim SJ, Miller JL, Kuipers PJ, German JR, Beaudet AL, Sahoo T, Driscoll DJ. Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes. Eur J Hum Genet. 2012;20(3):283\u201390.","journal-title":"Eur J Hum Genet"},{"issue":"4","key":"2439_CR21","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1007\/s00335-007-9019-3","volume":"18","author":"EG Peery","year":"2007","unstructured":"Peery EG, Elmore MD, Resnick JL, Brannan CI, Johnstone KA. A targeted deletion upstream of Snrpn does not result in an imprinting defect. Mamm Genome. 2007;18(4):255\u201362.","journal-title":"Mamm Genome"},{"issue":"Database issue","key":"2439_CR22","doi-asserted-by":"publisher","first-page":"D157","DOI":"10.1093\/nar\/gks1233","volume":"41","author":"R Dreos","year":"2013","unstructured":"Dreos R, Ambrosini G, Cavin Perier R, Bucher P. EPD and EPDnew, high-quality promoter resources in the next-generation sequencing era. Nucleic Acids Res. 2013;41(Database issue):D157\u2013164.","journal-title":"Nucleic Acids Res"},{"issue":"18","key":"2439_CR23","doi-asserted-by":"publisher","first-page":"5109","DOI":"10.1016\/S0021-9258(18)38271-1","volume":"273","author":"R Seifert","year":"1998","unstructured":"Seifert R, Wenzel-Seifert K, Lee TW, Gether U, Sanders-Bush E, Kobilka BK. Different effects of Gsalpha splice variants on beta2-adrenoreceptor-mediated signaling. The Beta2-adrenoreceptor coupled to the long splice variant of Gsalpha has properties of a constitutively active receptor. J Biol Chem. 1998;273(18):5109\u201316.","journal-title":"J Biol Chem"},{"key":"2439_CR24","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s12868-015-0178-y","volume":"16","author":"RJ Donati","year":"2015","unstructured":"Donati RJ, Schappi J, Czysz AH, Jackson A, Rasenick MM. Differential effects of antidepressants escitalopram versus lithium on Gs alpha membrane relocalization. BMC Neurosci. 2015;16:40.","journal-title":"BMC Neurosci"},{"issue":"2","key":"2439_CR25","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1074\/jbc.275.2.1327","volume":"275","author":"DS Evanko","year":"2000","unstructured":"Evanko DS, Thiyagarajan MM, Wedegaertner PB. Interaction with Gbetagamma is required for membrane targeting and palmitoylation of Galpha(s) and Galpha(q). J Biol Chem. 2000;275(2):1327\u201336.","journal-title":"J Biol Chem"}],"container-title":["BMC Medical Genomics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-026-02439-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-026-02439-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12920-026-02439-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:06:54Z","timestamp":1792721214000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12920-026-02439-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,28]]},"references-count":25,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2439"],"URL":"https:\/\/doi.org\/10.1186\/s12920-026-02439-x","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-9510855\/v1","asserted-by":"object"}]},"ISSN":["1755-8794"],"issn-type":[{"value":"1755-8794","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,28]]},"assertion":[{"value":"23 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The use of human samples was reviewed and approved by the Institutional Review Board of Samsung Medical Center in Seoul, South Korea. Informed consent was obtained from all the patients or relatives to participate in this study according to the research ethics guidelines. (IRB: 2012-05-080).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"160"}}