title: Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas.
abstract: 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 (Thyroid tumour with Cell Oxyphilia) 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.
authors.affiliation: Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Università di Bologna, Bologna, Italy. elena.bonora@eurogene.org
authors.forename: E
authors.initials: E
authors.lastname: Bonora
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.forename: F
authors.initials: F
authors.lastname: Bonichon
authors.forename: G
authors.initials: G
authors.lastname: Tallini
authors.forename: G
authors.initials: G
authors.lastname: Romeo
mesh_terms: D018249:Adenoma, Oxyphilic / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D051336:Mitochondrial Membranes / Q000473:pathology; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D013964:Thyroid Neoplasms / Q000235:genetics*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C489671:TIMM44 protein, human