Identification of a novel TTC19 mutation in a Portuguese family with complex II...

• Autor(es): Nogueira, Célia ; Barros, José ; Sá, Maria José ; Azevedo, Luisa ; Santorelli, Filippo ; Vilarinho, Laura
• Data: 2012
• Identificador Persistente: http://hdl.handle.net/10400.18/1196
• Origem: Repositório Científico do Instituto Nacional de Saúde
• Assunto(s): CIII; Doenças Genéticas
• Tipo de Documento: Documento de conferência
• Idioma: Inglês

Descrição

Publicado em: Livro de abstracts do congresso UMDF - 2012 Defects of mitochondrial complex III (CIII) are a relatively rare cause of mitochondrial dysfunction. CIII or ubiquinol-cytochrome c reductase is the third component of the mitochondrial respiratory chain and catalyzes the electrons transfer from reduced coenzyme Q to cytochrome c and is composed of 11 subunits; one encoded by mitochondrial DNA (MT-CYB) and the remaining by nuclear genes. BCS1L gene is a CIII assembly factor. Mutations in MT-CYB and BCS1L genes account for the vast majority of mutations leading to CIII deficiency, and are associated with a wide range of neuromuscular disorders. The human tetratricopeptide 19 (TTC19), encodes a poorly understood member of tetratricopeptide repeat domain 19 located on chromosome 17 and appears to be involved in the correct assembly of CIII. Recently, mutations in TTC19 have been described in three unrelated Italian kindred in association with a severe neurodegenerative disease. Here we present a consanguineous Portuguese family where a severe biochemical deficiency of complex III enzyme activity occurred in four siblings in association with neurological manifestations suggestive of cerebellar ataxia combined with relentless psychiatric manifestations. Variability in age at onset and disease course was associated with a novel homozygous mutation in TTC19. We had first detected a biochemically deficient enzyme activity in the family, we had analyzed all structural genes part of CIII as well as BCS1L. Only the recent description of mutations in TTC19 raised high the suspect of a similar condition in the present family. The novel TTC19 mutation identified in this family, was homozygous in the four patients, heterozygous in their parents and in two healthy relatives, and it was absent in ethnically-matched controls. The mutation predicts a frameshift, resulting in a truncated protein by the insertion of a premature stop codon. In summary, we are describing the 4th family identified in the world carrying a novel TTC19 mutation. Our data corroborate the genotype and phenotype variability presented by the affected family members and hopefully will contribute to a deeper understanding of the CIII-related disorders.