title: Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency.
abstract: 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.
authors.affiliation: Department of Genetics, National Institute of Health, INSA, Porto, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Nogueira
authors.forename: José
authors.initials: J
authors.lastname: Barros
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Sá
authors.forename: Luísa
authors.initials: L
authors.lastname: Azevedo
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.forename: Alessandra
authors.initials: A
authors.lastname: Torraco
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Meschini
authors.forename: Daniela
authors.initials: D
authors.lastname: Verrigni
authors.forename: Claudia
authors.initials: C
authors.lastname: Nesti
authors.forename: Teresa
authors.initials: T
authors.lastname: Rizza
authors.forename: João
authors.initials: J
authors.lastname: Teixeira
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.forename: Manuel Melo
authors.initials: MM
authors.lastname: Pires
authors.forename: Laura
authors.initials: L
authors.lastname: Vilarinho
authors.forename: Filippo M
authors.initials: FM
authors.lastname: Santorelli
mesh_terms: D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D017237:Mitochondrial Encephalomyopathies / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C557528:TTC19 protein, human