Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.

TitleMutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.
Publication TypeJournal Article
Year of Publication2011
AuthorsGhezzi, D, Arzuffi, P, Zordan, M, Da Re, C, Lamperti, C, Benna, C, D'Adamo, P, Diodato, D, Costa, R, Mariotti, C, Uziel, G, Smiderle, C, Zeviani, M
JournalNat Genet
Date Published2011 Mar
KeywordsAdult, Animals, Brain, Codon, Nonsense, Drosophila melanogaster, Electron Transport Complex III, Female, Gene Knockdown Techniques, Humans, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Nervous System Diseases

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.

Alternate JournalNat. Genet.
Citation Key10.1038/ng.761
PubMed ID21278747
Grant ListGGP07019 / / Telethon / Italy
GPP10005 / / Telethon / Italy
GTB07001 / / Telethon / Italy