title: Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To examine the prevalence and spectrum of FP/TMEM127 mutations in pheochromocytomas and paragangliomas and to test the effect of mutations in vitro.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Hematology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascon
authors.forename: Yuejuan
authors.initials: Y
authors.lastname: Qin
authors.forename: Lucia
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: King
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Toledo
authors.forename: Tonino
authors.initials: T
authors.lastname: Ercolino
authors.forename: Elena
authors.initials: E
authors.lastname: Rapizzi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ricketts
authors.forename: Luigi
authors.initials: L
authors.lastname: Mori
authors.forename: Mara
authors.initials: M
authors.lastname: Giacchè
authors.forename: Antonella
authors.initials: A
authors.lastname: Mendola
authors.forename: Elisa
authors.initials: E
authors.lastname: Taschin
authors.forename: Francesca
authors.initials: F
authors.lastname: Boaretto
authors.forename: Paola
authors.initials: P
authors.lastname: Loli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Iacobone
authors.forename: Gian-Paolo
authors.initials: GP
authors.lastname: Rossi
authors.forename: Bernadette
authors.initials: B
authors.lastname: Biondi
authors.forename: José Viana
authors.initials: JV
authors.lastname: Lima-Junior
authors.forename: Claudio E
authors.initials: CE
authors.lastname: Kater
authors.forename: Marie
authors.initials: M
authors.lastname: Bex
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Grossman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
authors.forename: Marta
authors.initials: M
authors.lastname: Barontini
authors.forename: Alexandre
authors.initials: A
authors.lastname: Persu
authors.forename: Maurizio
authors.initials: M
authors.lastname: Castellano
authors.forename: Sergio P A
authors.initials: SP
authors.lastname: Toledo
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics* / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C548370:TMEM127 protein, human