Objetivo We have recently identified the molecular genetic cause of a puzzling clinical syndrome, initially termed “benign infantile mitochondrial myopathy due to reversible cytochrome c oxidase (COX) deficiency”. While childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions with fatal outcome, this syndrome stands out by showing complete (or almost complete) spontaneous recovery. We have detected the homoplasmic m.14674T>C mutation in the mitochondrial mt-tRNAGlu gene in 17 affected individuals from 12 independent families of different ethnic origins. The m.14674T>C mutation affects the discriminator base of mt-tRNAGlu, the last base at the 3´-end of the molecule, where the amino acid via the terminal CCA is attached, therefore thought to impair mitochondrial translation, as reflected by the COX-negative fibres and the multiple respiratory chain defects in skeletal muscle. The spontaneous recovery of the patients suggests the existence of so far unknown cellular compensatory mechanisms.We will investigate, i) why patients with reversible COX deficiency show an isolated muscle involvement, ii) why symptoms start uniformly in the first days or weeks of life, iii) what is the molecular basis of the age-dependent, spontaneous recovery, and iv) which factors influence mitochondrial protein synthesis in human cells, skeletal muscle and different tissues. We will study these factors in v) different types of mitochondrial disease.From a scientific standpoint, this is one of the few hereditary conditions with a life-threatening onset showing recovery. Finding a clearly pathogenic homoplasmic mtDNA mutation offers a new paradigm of mtDNA pathogenesis, and studying this unique disease may unveil factors that are important in other mitochondrial disease. The long-term goal would be to upregulate or boost compensatory factors in patients with mitochondrial disease with the aim to open new avenues for therapy. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsmutationnatural scienceschemical sciencesorganic chemistryamines Programa(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) ERC-SG-LS4 - ERC Starting Grant - Physiology, Pathophysiology and Endocrinology Convocatoria de propuestas ERC-2012-StG_20111109 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-SG - ERC Starting Grant Institución de acogida UNIVERSITY OF NEWCASTLE UPON TYNE Aportación de la UE € 1 432 075,00 Dirección KINGS GATE NE1 7RU Newcastle Upon Tyne Reino Unido Ver en el mapa Región North East (England) Northumberland and Tyne and Wear Tyneside Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Amanda Gregory (Dr.) Investigador principal Rita Horvath (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo UNIVERSITY OF NEWCASTLE UPON TYNE Reino Unido Aportación de la UE € 1 432 075,00 Dirección KINGS GATE NE1 7RU Newcastle Upon Tyne Ver en el mapa Región North East (England) Northumberland and Tyne and Wear Tyneside Tipo de actividad Higher or Secondary Education Establishments Contacto administrativo Amanda Gregory (Dr.) Investigador principal Rita Horvath (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos