{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:20:06Z","timestamp":1783592406458,"version":"3.55.0"},"reference-count":43,"publisher":"Bioscientifica","issue":"6","funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA016058, P01CA124570"],"award-info":[{"award-number":["P30CA016058, P01CA124570"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Germline mutations in the four genes (SDHA, SDHB, SDHC and SDHD) encoding the succinate dehydrogenase (SDH) holoenzyme are known to predispose towards the development of tumor including pheochromocytomas\/paragangliomas (PPGLs), gastrointestinal stromal tumors (GISTs), clear cell renal cancers (RCC) and possibly others. Mutations in these genes have also been described in patients with Cowden syndrome, which includes tumors of the breast, brain and thyroid gland. Although nonsense mutations are clearly pathogenic, the functional consequences of many missense mutations are unclear. It has previously been reported that the missense mutations SDHDG12S and SDHDH50R predispose to thyroid and breast cancers, although this characterization has been disputed. To address this question, we developed mouse models to test tumorigenicity of these variants. The reference mouse genome codes for a serine at residue 12 in Sdhd, so this variant was not pursued further. To assess the role of SDHDH50R (H50R), we generated a knock-in mouse allele for this variant and studied its effects in vivo as well as in vitro in mouse embryonic fibroblasts. Unlike null alleles for Sdhd, the H50R allele did not produce embryonic lethality when homozygous. There was no statistically significant difference in survival or tumor formation in homozygous or heterozygous animals compared to littermate controls. In vitro studies similarly failed to detect significant differences in proliferation, colony formation or metabolic function. Based on our analysis of this allele\u2019s function both in vivo and in vitro, we conclude that the SDHDH50R allele is most likely a non-pathogenic polymorphism.<\/jats:p>","DOI":"10.1530\/erc-24-0337","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T12:03:57Z","timestamp":1745496237000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":0,"title":["<i>In vivo<\/i>\n                    and\n                    <i>in vitro<\/i>\n                    analysis of functional effects of the SDHD H50R variant"],"prefix":"10.1530","volume":"32","author":[{"given":"Shivam","family":"Priya","sequence":"first","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University 1 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Chakravarthy","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University 1 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Ziegler","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University 1 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Vesco","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University 1 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"La Perle","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, The Ohio State University 2 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, The Ohio State University 3 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6180-342X","authenticated-orcid":true,"given":"Lawrence S","family":"Kirschner","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics, The Ohio State University 1 , , ,","place":["Columbus, Ohio, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"2026070905424755800_bib16","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"1000 Genomes Project Consortium","year":"2015","journal-title":"Nature"},{"key":"2026070905424755800_bib1","first-page":"e41","article-title":"A comparison of strategies for immortalizing mouse embryonic fibroblasts","volume":"3","author":"Amand","year":"2016","journal-title":"J Biol Methods"},{"key":"2026070905424755800_bib2","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s13238-017-0451-1","article-title":"The emerging role and targetability of the TCA cycle in cancer metabolism","volume":"9","author":"Anderson","year":"2018","journal-title":"Protein Cell"},{"key":"2026070905424755800_bib3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.21037\/gs.2019.10.25","article-title":"Pheochromocytoma\/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options","volume":"9","author":"Antonio","year":"2020","journal-title":"Gland Surg"},{"key":"2026070905424755800_bib4","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1530\/ERC-17-0229","article-title":"Sdhd ablation promotes thyroid tumorigenesis by inducing a stem-like phenotype","volume":"24","author":"Ashtekar","year":"2017","journal-title":"Endocr Relat Cancer"},{"key":"2026070905424755800_bib7","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.ajhg.2010.12.016","article-title":"Succinate dehydrogenase gene variants and their role in Cowden syndrome","volume":"88","author":"Bayley","year":"2011","journal-title":"Am J Hum Genet"},{"key":"2026070905424755800_bib5","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/1471-2350-6-39","article-title":"The SDH mutation database: an online resource for succinate dehydrogenase sequence variants involved in pheochromocytoma, paraganglioma and mitochondrial complex II deficiency","volume":"6","author":"Bayley","year":"2005","journal-title":"BMC Med Genet"},{"key":"2026070905424755800_bib6","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0007987","article-title":"Sdhd and SDHD\/H19 knockout mice do not develop paraganglioma or pheochromocytoma","volume":"4","author":"Bayley","year":"2009","journal-title":"PLoS One"},{"key":"2026070905424755800_bib8","article-title":"The soft agar colony formation assay","volume":"92","author":"Borowicz","year":"2014","journal-title":"J Vis Exp"},{"key":"2026070905424755800_bib9","doi-asserted-by":"crossref","DOI":"10.1016\/j.beem.2020.101416","article-title":"An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma","volume":"34","author":"Buffet","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026070905424755800_bib10","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1158\/2159-8290.CD-13-0083","article-title":"Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities","volume":"3","author":"Cairns","year":"2013","journal-title":"Cancer Discov"},{"key":"2026070905424755800_bib11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41586-023-06045-0","article-title":"A genomic mutational constraint map using variation in 76,156 human genomes","volume":"625","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"2026070905424755800_bib12","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/s11910-013-0345-4","article-title":"IDH1 and IDH2 mutations in gliomas","volume":"13","author":"Cohen","year":"2013","journal-title":"Curr Neurol Neurosci Rep"},{"key":"2026070905424755800_bib13","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.semcdb.2019.04.013","article-title":"Regulation of succinate dehydrogenase and role of succinate in cancer","volume":"98","author":"Dalla Pozza","year":"2020","journal-title":"Semin Cell Dev Biol"},{"key":"2026070905424755800_bib14","first-page":"171","article-title":"Hereditary paraganglioma\/pheochromocytoma and inherited succinate dehydrogenase deficiency","volume":"63","author":"Favier","year":"2005","journal-title":"Horm Res"},{"key":"2026070905424755800_bib15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ymgme.2020.09.009","article-title":"The genetic basis of isolated mitochondrial complex II deficiency","volume":"131","author":"Fullerton","year":"2020","journal-title":"Mol Genet Metab"},{"key":"2026070905424755800_bib17","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1097\/WCO.0b013e32834cd415","article-title":"Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target","volume":"24","author":"Guo","year":"2011","journal-title":"Curr Opin Neurol"},{"key":"2026070905424755800_bib18","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1038\/s41416-020-0814-x","article-title":"IDH mutation in glioma: molecular mechanisms and potential therapeutic targets","volume":"122","author":"Han","year":"2020","journal-title":"Br J Cancer"},{"key":"2026070905424755800_bib19","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10689-010-9402-1","article-title":"Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma","volume":"10","author":"Hensen","year":"2011","journal-title":"Fam Cancer"},{"key":"2026070905424755800_bib20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1097\/GIM.0b013e3181ac9aea","article-title":"PTEN hamartoma tumor syndrome: an overview","volume":"11","author":"Hobert","year":"2009","journal-title":"Genet Med"},{"key":"2026070905424755800_bib21","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.beem.2010.04.001","article-title":"SDH-related pheochromocytoma and paraganglioma","volume":"24","author":"Kantorovich","year":"2010","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"2026070905424755800_bib22","doi-asserted-by":"crossref","first-page":"13189","DOI":"10.1096\/fj.201802655RR","article-title":"A conditional mouse model of complex II deficiency manifesting as Leigh-like syndrome","volume":"33","author":"Khazal","year":"2019","journal-title":"FASEB J"},{"key":"2026070905424755800_bib23","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.mce.2015.06.027","article-title":"From Nf1 to Sdhb knockout: successes and failures in the quest for animal models of pheochromocytoma","volume":"421","author":"Lepoutre-Lussey","year":"2016","journal-title":"Mol Cell Endocrinol"},{"key":"2026070905424755800_bib24","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.ccr.2013.04.018","article-title":"SDH mutations establish a hypermethylator phenotype in paraganglioma","volume":"23","author":"Letouze","year":"2013","journal-title":"Cancer Cell"},{"key":"2026070905424755800_bib25","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/s41431-021-00887-w","article-title":"Consolidating biallelic SDHD variants as a cause of mitochondrial complex II deficiency","volume":"29","author":"Lin","year":"2021","journal-title":"Eur J Hum Genet"},{"key":"2026070905424755800_bib26","doi-asserted-by":"crossref","first-page":"R157","DOI":"10.1530\/ERC-22-0157","article-title":"Succinate dehydrogenase and MYC-associated factor X mutations in pituitary neuroendocrine tumours","volume":"29","author":"Loughrey","year":"2022","journal-title":"Endocr Relat Cancer"},{"key":"2026070905424755800_bib27","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1002\/cncr.29106","article-title":"Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study","volume":"121","author":"Mahdi","year":"2015","journal-title":"Cancer"},{"key":"2026070905424755800_bib28","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/7651_2019_259","article-title":"Scratch wound healing assay","volume":"2109","author":"Martinotti","year":"2020","journal-title":"Methods Mol Biol"},{"key":"2026070905424755800_bib29","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s12022-022-09704-6","article-title":"Overview of the 2022 WHO classification of paragangliomas and pheochromocytomas","volume":"33","author":"Mete","year":"2022","journal-title":"Endocr Pathol"},{"key":"2026070905424755800_bib30","doi-asserted-by":"crossref","first-page":"10307","DOI":"10.1158\/0008-5472.CAN-05-3183","article-title":"Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins","volume":"65","author":"Nadella","year":"2005","journal-title":"Cancer Res"},{"key":"2026070905424755800_bib31","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ajhg.2008.07.011","article-title":"Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes","volume":"83","author":"Ni","year":"2008","journal-title":"Am J Hum Genet"},{"key":"2026070905424755800_bib32","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1093\/hmg\/ddr459","article-title":"Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD\/NAD-dependant destabilization of p53","volume":"21","author":"Ni","year":"2012","journal-title":"Hum Mol Genet"},{"key":"2026070905424755800_bib33","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/modpathol.2015.41","article-title":"SDHB\/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T)","volume":"28","author":"Papathomas","year":"2015","journal-title":"Mod Pathol"},{"key":"2026070905424755800_bib34","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1210\/me.2007-0369","article-title":"Mutation of Prkar1a causes osteoblast neoplasia driven by dysregulation of protein kinase A","volume":"22","author":"Pavel","year":"2008","journal-title":"Mol Endocrinol"},{"key":"2026070905424755800_bib35","doi-asserted-by":"crossref","first-page":"10933","DOI":"10.1128\/MCB.24.24.10933-10940.2004","article-title":"The mitochondrial SDHD gene is required for early embryogenesis, and its partial deficiency results in persistent carotid body glomus cell activation with full responsiveness to hypoxia","volume":"24","author":"Piruat","year":"2004","journal-title":"Mol Cell Biol"},{"key":"2026070905424755800_bib36","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1530\/ERC-11-0306","article-title":"Thyroid-specific ablation of the Carney complex gene, PRKAR1A, results in hyperthyroidism and follicular thyroid cancer","volume":"19","author":"Pringle","year":"2012","journal-title":"Endocr Relat Cancer"},{"key":"2026070905424755800_bib37","doi-asserted-by":"crossref","first-page":"3903","DOI":"10.1210\/jc.2014-2151","article-title":"Krebs cycle metabolite profiling for identification and stratification of pheochromocytomas\/paragangliomas due to succinate dehydrogenase deficiency","volume":"99","author":"Richter","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"2026070905424755800_bib38","first-page":"221","article-title":"The genetics of Leigh syndrome and its implications for clinical practice and risk management","volume":"7","author":"Ruhoy","year":"2014","journal-title":"Appl Clin Genet"},{"key":"2026070905424755800_bib39","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1093\/jnen\/nly042","article-title":"Sdha+\/\u2212 rats display minimal muscle pathology without significant behavioral or biochemical abnormalities","volume":"77","author":"Siebers","year":"2018","journal-title":"J Neuropathol Exp Neurol"},{"key":"2026070905424755800_bib40","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0232565","article-title":"An image J plugin for the high throughput image analysis of in vitro scratch wound healing assays","volume":"15","author":"Suarez-Arnedo","year":"2020","journal-title":"PLoS One"},{"key":"2026070905424755800_bib41","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/S1470-2045(09)70164-0","article-title":"An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis","volume":"10","author":"Van Nederveen","year":"2009","journal-title":"Lancet Oncol"},{"key":"2026070905424755800_bib42","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1097\/MED.0000000000000634","article-title":"Genetics of pheochromocytoma and paraganglioma","volume":"28","author":"Wachtel","year":"2021","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"2026070905424755800_bib43","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1093\/hmg\/ddu425","article-title":"Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation","volume":"24","author":"Yu","year":"2015","journal-title":"Hum Mol Genet"}],"container-title":["Endocrine-Related Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/32\/6\/ERC-24-0337.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/32\/6\/ERC-24-0337.xml","content-type":"text\/html","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-24-0337\/246960\/erc-24-0337.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article-pdf\/doi\/10.1530\/ERC-24-0337\/246960\/erc-24-0337.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T09:42:56Z","timestamp":1783590176000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.bioscientifica.com\/erc\/article\/32\/6\/e240337\/25909\/In-vivo-and-in-vitro-analysis-of-functional"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,24]]},"references-count":43,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6,1]]}},"URL":"https:\/\/doi.org\/10.1530\/erc-24-0337","relation":{},"ISSN":["1479-6821","1351-0088"],"issn-type":[{"value":"1479-6821","type":"electronic"},{"value":"1351-0088","type":"print"}],"subject":[],"published":{"date-parts":[[2025,4,24]]},"article-number":"e240337"}}