2026-05-22T02:50:18Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260532025-12-18T12:56:05Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Remacha, Laura author Currás-Freixes, Maria author Torres-Ruiz, Raúl author Schiavi, Francesca author Torres-Pérez, Rafael author Calsina, Bruna author Letón, Rocío author Comino-Méndez, Iñaki author Roldán-Romero, Juan M author Montero-Conde, Cristina author Santos, María author Pérez, Lucía Inglada author Pita, Guillermo author Alonso, María R author Honrado, Emiliano author Pedrinaci, Susana author Crespo-Facorro, Benedicto author Percesepe, Antonio author Falcioni, Maurizio author Rodríguez-Perales, Sandra author Korpershoek, Esther author Ramón-Maiques, Santiago author Opocher, Giuseppe author Rodríguez-Antona, Cristina author Robledo Batanero, Mercedes author Cascon Soriano, Alberto author 2018-12 The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors. Whole-exome sequencing was applied to the germlines of a parent-proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed. We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma. Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition. Genet Med . 2018 Dec;20(12):1644-1651 Genet Med 29740169 https://hdl.handle.net/20.500.12105/26053 CRISPR/Cas9 gene editing DNMT3A exome sequencing hypermethylation paraganglioma Gain-of-function mutations in DNMT3A in patients with paraganglioma.