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

Daniele Ghezzi, Paola Arzuffi, Mauro Zordan, Caterina Da Re, Costanza Lamperti, Clara Benna, Pio D'Adamo, Daria Diodato, Rodolfo Costa, Caterina Mariotti, Graziella Uziel, Cristina Smiderle, Massimo Zeviani

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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.

Original languageEnglish
Pages (from-to)259-263
Number of pages5
JournalNature Genetics
Volume43
Issue number3
DOIs
Publication statusPublished - Mar 2011

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ASJC Scopus subject areas

  • Genetics

Cite this

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. Nature Genetics, 43(3), 259-263. https://doi.org/10.1038/ng.761