Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

• Published in: British journal of cancer 2006-12, Vol.95 (11), p.1529-1536
• Main Authors: Bonora, E, Evangelisti, C, Bonichon, F, Tallini, G, Romeo, G
• Format: Article
• Language: English
• Subjects: Adenoma, Oxyphilic - genetics; Amino Acid Sequence; Animals; Apoptosis; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carrier Proteins - genetics; Chromosomes, Human, Pair 19 - genetics; Drug Resistance; Endocrinopathies; Epidemiology; Female; Genes; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Iodine; Male; Malignant tumors; Medical research; Medical sciences; Membrane Proteins - genetics; Mitochondria; Mitochondrial DNA; Mitochondrial Membrane Transport Proteins; Mitochondrial Membranes - pathology; Mitochondrial Precursor Protein Import Complex Proteins; Mitochondrial Proteins - genetics; Molecular Diagnostics; Molecular Medicine; Molecular Sequence Data; Mutation; Oncology; Pedigree; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sequence Homology, Amino Acid; Thyroid cancer; Thyroid Neoplasms - genetics; Thyroid. Thyroid axis (diseases); Transfection; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6603455

Familial Non-Medullary Thyroid Carcinoma (fNMTC) represents 3–7% of all thyroid tumours and is associated with some of the highest familial risks among all cancers, with an inheritance pattern compatible with an autosomal dominant model with reduced penetrance. We previously mapped a predisposing locus, TCO ( T hyroid tumour with C ell O xyphilia) on chromosome 19p13.2, for a particular form of thyroid tumour characterised by cells with an abnormal proliferation of mitochondria (oxyphilic or oncocytic cells). In the present work, we report the systematic screening of 14 candidate genes mapping to the region of linkage in affected TCO members, that led us to identify two novel variants respectively in exon 9 and exon 13 of TIMM44 , a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumour development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO.