title: Identical germline mutations in the TMEM127 gene in two unrelated Japanese patients with bilateral pheochromocytoma.
abstract: OBJECTIVE
  Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects.
  
  
  METHODS
  For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls.
  
  
  RESULTS
  Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation.
  
  
  CONCLUSIONS
  This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Nippon Medical School, Tsukuba, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Takeichi
authors.forename: Sanae
authors.initials: S
authors.lastname: Midorikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Banyar Than
authors.initials: BT
authors.lastname: Naing
authors.forename: Hideki
authors.initials: H
authors.lastname: Tamura
authors.forename: Toshiko
authors.initials: T
authors.lastname: Wakakuri-Kano
authors.forename: Akira
authors.initials: A
authors.lastname: Ishizaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sugihara
authors.forename: Sumiko
authors.initials: S
authors.lastname: Nissato
authors.forename: Yuria
authors.initials: Y
authors.lastname: Saito
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Aita
authors.forename: Kiyo-aki
authors.initials: KA
authors.lastname: Ishii
authors.forename: Takehito
authors.initials: T
authors.lastname: Igarashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Hisato
authors.initials: H
authors.lastname: Hara
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ikeda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Shinichi
authors.initials: S
authors.lastname: Oikawa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takekoshi
mesh_terms: D000328:Adult; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007564:Japan; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010673:Pheochromocytoma / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; C548370:TMEM127 protein, human