2026-04-29T22:57:43Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260582025-12-18T12:55:46Zcom_20.500.12105_2273com_20.500.12105_2202col_20.500.12105_19571

00925njm 22002777a 4500 dc Yao, Li author Schiavi, Francesca author Cascon Soriano, Alberto author Qin, Yuejuan author Inglada-Pérez, Lucia author King, Elizabeth E author Toledo, Rodrigo A author Ercolino, Tonino author Rapizzi, Elena author Ricketts, Christopher J author Mori, Luigi author Giacchè, Mara author Mendola, Antonella author Taschin, Elisa author Boaretto, Francesca author Loli, Paola author Iacobone, Maurizio author Rossi, Gian-Paolo author Biondi, Bernadette author Lima-Junior, José Viana author Kater, Claudio E author Bex, Marie author Vikkula, Miikka author Grossman, Ashley B author Gruber, Stephen B author Barontini, Marta author Persu, Alexandre author Castellano, Maurizio author Toledo, Sergio P A author Maher, Eamonn R author Mannelli, Massimo author Opocher, Giuseppe author Robledo Batanero, Mercedes author Dahia, Patricia L M author 2010-12-15 Pheochromocytomas and paragangliomas are genetically heterogeneous neural crest-derived neoplasms. We recently identified germline mutations of the novel transmembrane-encoding gene FP/TMEM127 in familial and sporadic pheochromocytomas consistent with a tumor suppressor effect. To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. We sequenced the FP/TMEM127 gene in 990 individuals with pheochromocytomas and/or paragangliomas, including 898 previously unreported cases without mutations in other susceptibility genes from 8 independent worldwide referral centers between January 2009 and June 2010. A multiplex polymerase chain reaction-based method was developed to screen for large gene deletions in 545 of these samples. Confocal microscopy of 5 transfected mutant proteins was used to determine their subcellular localization. The frequency and type of FP/TMEM127 mutation or deletion was assessed and correlated with clinical variables; the subcellular localization of 5 overexpressed mutants was compared with wild-type FP/TMEM127 protein. We identified 19 potentially pathogenic FP/TMEM127 germline mutations in 20 independent families, but no large deletions were detected. All mutation carriers had adrenal tumors, including 7 bilateral (P = 2.7 × 10(-4)) and/or with familial disease (5 of 20 samples; P = .005). The median age at disease onset in the FP/TMEM127 mutation group was similar to that of patients without a mutation (41.5 vs 45 years, respectively; P = .54). The most common presentation was that of a single benign adrenal tumor in patients older than 40 years. Malignancy was seen in 1 mutation carrier (5%). Expression of 5 novel FP/TMEM127 mutations in cell lines revealed diffuse localization of the mutant proteins in contrast with the discrete multiorganelle distribution of wild-type TMEM127. Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occurred in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein. JAMA 21156949 https://hdl.handle.net/20.500.12105/26058 TUMOR-SUPPRESSOR1P36 SUSCEPTIBILITY 1P36 Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.