title: Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.
abstract: Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.
authors.affiliation: Unit of Molecular Neurogenetics, The Foundation 'Carlo Besta' Institute of Neurology, Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Paola
authors.initials: P
authors.lastname: Arzuffi
authors.forename: Mauro
authors.initials: M
authors.lastname: Zordan
authors.forename: Caterina
authors.initials: C
authors.lastname: Da Re
authors.forename: Costanza
authors.initials: C
authors.lastname: Lamperti
authors.forename: Clara
authors.initials: C
authors.lastname: Benna
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Costa
authors.forename: Caterina
authors.initials: C
authors.lastname: Mariotti
authors.forename: Graziella
authors.initials: G
authors.lastname: Uziel
authors.forename: Cristina
authors.initials: C
authors.lastname: Smiderle
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
mesh_terms: D000328:Adult; D000818:Animals; D001921:Brain / Q000473:pathology; D018389:Codon, Nonsense; D004331:Drosophila melanogaster / Q000235:genetics; D014450:Electron Transport Complex III / Q000172:deficiency* / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C557528:TTC19 protein, human; D014450:Electron Transport Complex III