title: Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid.
abstract: Oxyphil or Hurthle cell tumours of the thyroid are characterised by their consistent excessive number of mitochondria. A recently discovered gene, GRIM-19 has been found to fulfil two roles within the cell: as a member of the interferon-beta and retinoic acid-induced pathway of cell death, and as part of the mitochondrial Complex I assembly. In addition, a gene predisposing to thyroid tumours with cell oxyphilia (TCO) has been mapped to chromosome 19p13.2 in one family. A cluster of genes involved in mitochondrial metabolism occurs in this region; one of these is GRIM-19. We have searched for GRIM-19 mutations in a series of 52 thyroid tumours. Somatic missense mutations in GRIM-19 were detected in three of 20 sporadic Hurthle cell carcinomas. A germline mutation was detected in a Hurthle cell papillary carcinoma arising in a thyroid with multiple Hurthle cell nodules. No mutations were detected in any of the 20 non-Hurthle cell carcinomas tested, nor in any of 96 blood donor samples. In one of the sporadic Hurthle cell papillary carcinomas positive for GRIM-19 mutation, we have also detected a ret/PTC-1 rearrangement. No GRIM-19 mutations were detected in any of the six cases of known familial Hurthle cell tumour tested, so that our results do not support the identification of GRIM-19 as the TCO gene. The GRIM-19 mutations we have detected are the first nuclear gene mutations specific to Hurthle cell tumours to be reported to date; we propose that such mutations can be involved in the genesis of sporadic or familial Hurthle cell tumours through the dual function of GRIM-19 in mitochondrial metabolism and cell death.
authors.affiliation: IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal.
authors.forename: V
authors.initials: V
authors.lastname: Máximo
authors.forename: T
authors.initials: T
authors.lastname: Botelho
authors.forename: J
authors.initials: J
authors.lastname: Capela
authors.forename: P
authors.initials: P
authors.lastname: Soares
authors.forename: J
authors.initials: J
authors.lastname: Lima
authors.forename: A
authors.initials: A
authors.lastname: Taveira
authors.forename: T
authors.initials: T
authors.lastname: Amaro
authors.forename: A P
authors.initials: AP
authors.lastname: Barbosa
authors.forename: A
authors.initials: A
authors.lastname: Preto
authors.forename: H R
authors.initials: HR
authors.lastname: Harach
authors.forename: D
authors.initials: D
authors.lastname: Williams
authors.forename: M
authors.initials: M
authors.lastname: Sobrinho-Simões
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics* / Q000503:physiopathology*; D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D008969:Molecular Sequence Data; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics*; D021122:Protein Subunits; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D021122:Protein Subunits; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf