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

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

Impacts of mine closure in Doncaster: an index of social stress

This study uses administrative data to characterise small areas within Doncaster, South Yorkshire, a location affected by mine colliery closures. The use of administrative data is motivated by questions about the future of the UK’s Census. Following the 2011 Census, the ‘Beyond 2011’ programme was established by the Office for National Statistics to assess the feasibility of using administrative statistics as an alternative to the census in England and Wales. Informed by Beyond 2011, the National Statistician recommended that there will be a 2021 Census but that the country’s statistical system should be enhanced by greater use of administrative data. An index is developed here relevant to Doncaster which combines information obtained from administrative data on: the economic situation through jobseeker’s allowance claimant counts; health difficulties through incapacity and disability benefit claimants; and economic-gerontography based on the income dependency of the older population. The resulting index represents small area variations in social stress. Doncaster, like many coalfield areas, has seen the industry decline dramatically which has knock on effects to employment rates and health and to the ageing workforce. Summing three standardised variables which capture these dimensions into a single figure index has revealed small area variations in social stress. The result of this relatively simple approach has a close correspondence to the IMD’s sophistication

Reevaluation of the role of the Pam18:Pam16 interaction in translocation of proteins by the mitochondrial Hsp70-based import motor

Pam18, the J-protein cochaperone of the Hsp70-based mitochondrial import motor, forms a heterodimer with the structurally related protein Pam16. Genetic and biochemical studies suggest a critical role of this interaction in maintaining Pam18's association with the translocon rather than its previously proposed regulatory role

Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor

The import motor of the mitochondrial translocase of the inner membrane (TIM23) mediates the ATP-dependent translocation of preproteins into the mitochondrial matrix by cycles of binding to and release from mtHsp70. An essential step of this process is the stimulation of the ATPase activity of mtHsp70 performed by the J cochaperone Tim14. Tim14 forms a complex with the J-like protein Tim16. The crystal structure of this complex shows that the conserved domains of the two proteins have virtually identical folds but completely different surfaces enabling them to perform different functions. The Tim14-Tim16 dimer reveals a previously undescribed arrangement of J and J-like domains. Mutations that destroy the complex between Tim14 and Tim16 are lethal demonstrating that complex formation is an essential requirement for the viability of cells. We further demonstrate tight regulation of the cochaperone activity of Tim14 by Tim16. The first crystal structure of a J domain in complex with a regulatory protein provides new insights into the function of the mitochondrial TIM23 translocase and the Hsp70 chaperone system in general