Ghezzi, 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. (2011). Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies.  Nat. Genet. 43(3): 259--263.

FBrf0213121

Research paper

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.