Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas

Li Yao, Francesca Schiavi, Alberto Cascon, Yuejuan Qin, Lucia Inglada-Pérez, Elizabeth E. King, Rodrigo A. Toledo, Tonino Ercolino, Elena Rapizzi, Christopher J. Ricketts, Luigi Mori, Mara Giacchè, Antonella Mendola, Elisa Taschin, Francesca Boaretto, Paola Loli, Maurizio Iacobone, Gian Paolo Rossi, Bernadette Biondi, José Viana LimaClaudio E. Kater, Marie Bex, Miikka Vikkula, Ashley B. Grossman, Stephen B. Gruber, Marta Barontini, Alexandre Persu, Maurizio Castellano, Sergio P.A. Toledo, Eamonn R. Maher, Massimo Mannelli, Giuseppe Opocher, Mercedes Robledo, Patricia L.M. Dahia

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Context: 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. Objectives: To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro. Design, Setting, and Participants: 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. Main Outcome Measures: 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. Results: 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 1mutation 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. Conclusions: Germline mutations of FP/TMEM127 were associated with pheochromocytoma but not paraganglioma and occured in an age group frequently excluded from genetic screening algorithms. Disease-associated mutations disrupt intracellular distribution of the FP/TMEM127 protein.

Original languageEnglish (US)
Pages (from-to)2611-2619
Number of pages9
Issue number23
StatePublished - Dec 15 2010

ASJC Scopus subject areas

  • General Medicine


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