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

Yao, L; Schiavi, F; Cascon, A; Qin, Y; Inglada-Pérez, L; King, E; Toledo, R; Ercolino, T; Rapizzi, E; Ricketts, C; Mori, L; Giacchè, M; Mendola, A; Taschin, E; Boaretto, F; Loli, P; Iacobone, M; Rossi, G; Biondi, B; Lima-Junior, J; Kater, C; Bex, M; Vikkula, M; Grossman, AB; Gruber, S

Journal article

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

Abstract:: 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 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. CONCLUSIONS: 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.

Publication status:: Published

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APA Style

Yao, L., Schiavi, F., Cascon, A., Qin, Y., Inglada-Pérez, L., King, E., Toledo, R., Ercolino, T., Rapizzi, E., Ricketts, C., Mori, L., Giacchè, M., Mendola, A., Taschin, E., Boaretto, F., Loli, P., Iacobone, M., Rossi, G., Biondi, B., … Gruber, S. (2010). Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. JAMA, 304(23), 2611–2619.

MLA Style

Yao, L, et al. “Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas.” JAMA, vol. 304, no. 23, 2010, pp. 2611–19.

Chicago Style

Yao, L, F Schiavi, A Cascon, et al. 2010. “Spectrum and Prevalence of FP/TMEM127 Gene Mutations in Pheochromocytomas and Paragangliomas.” JAMA 304 (23): 2611–19.
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