{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T23:19:58Z","timestamp":1772579998804,"version":"3.50.1"},"reference-count":20,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T00:00:00Z","timestamp":1605139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"crossref","award":["2011\u20135025"],"award-info":[{"award-number":["2011\u20135025"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Nationale contre le Cancer","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Institut National du Cancer and the Direction G\u00e9n\u00e9rale de l\u2019Offre de Soins","award":["PRT-K 2014"],"award-info":[{"award-number":["PRT-K 2014"]}]},{"name":"Alliance Nationale pour les Sciences de la Vie et de la Sant\u00e9"},{"name":"National Alliance for Life Sciences & Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective\/design<\/jats:title>\n                  <jats:p>While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Patients and Setting<\/jats:title>\n                  <jats:p>Patients with a likely familial cancer burden of pheochromocytomas and\/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>While investigating unexplained PPGL cases, we identified a novel variant, c.1151C&amp;gt;T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G&amp;gt;A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A&amp;gt;G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa819","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T20:46:10Z","timestamp":1605213970000},"page":"459-471","source":"Crossref","is-referenced-by-count":8,"title":["Germline <i>DLST<\/i> Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4742-2708","authenticated-orcid":false,"given":"Alexandre","family":"Buffet","sequence":"first","affiliation":[{"name":"Universit\u00e9 de Paris, PARCC, INSERM, Equipe Labellis\u00e9e par la Ligue contre le Cancer, F-75015 Paris, France"},{"name":"Genetic department, Adrenal Referral Center, Assistance Publique-Ho\u0302pitaux de Paris (AP-HP), H\u00f4pital Europ\u00e9en Georges Pompidou, F-75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heggert","family":"Rebel","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9836-9137","authenticated-orcid":false,"given":"Eleonora P M","family":"Corssmit","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen C","family":"Jansen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4393-7421","authenticated-orcid":false,"given":"Erik F","family":"Hensen","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1155-0481","authenticated-orcid":false,"given":"Judith V M G","family":"Bov\u00e9e","sequence":"additional","affiliation":[{"name":"Department of Pathology, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aur\u00e9lien","family":"Morini","sequence":"additional","affiliation":[{"name":"Assistance Publique-Ho\u0302pitaux de Paris (AP-HP), Ho\u0302pital Europe\u0301en Georges Pompidou, De\u0301partement d\u2019anatomo-pathologie, F-75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4816-670X","authenticated-orcid":false,"given":"Anne-Paule","family":"Gimenez-Roqueplo","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, PARCC, INSERM, Equipe Labellis\u00e9e par la Ligue contre le Cancer, F-75015 Paris, France"},{"name":"Genetic department, Adrenal Referral Center, Assistance Publique-Ho\u0302pitaux de Paris (AP-HP), H\u00f4pital Europ\u00e9en Georges Pompidou, F-75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederik J","family":"Hes","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-2009","authenticated-orcid":false,"given":"Peter","family":"Devilee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands"},{"name":"Department of Pathology, Leiden University Medical Center, 2300 RC, Leiden, The 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