Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

• Autor(a) principal: Nogueira, C.
• Data de Publicação: 2013
• Outros Autores: Barros, J., Sá, M.J., Azevedo L, L., Taipa, R., Torraco, A., Meschini, M.C., Verrigni, D., Nesti, C., Rizza, T., Teixeira, João Paulo, Carrozzo, R., Pires, M.M., Vilarinho, L., Santorelli, F.M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/2220
• topic: Doenças Genéticas; Doenças Mitocondriais; Complex III; TTC19; Cerebellar Ataxia; Olivo–ponto–cerebellar Atrophy; Psychiatric Manifestations

Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.