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

Nature Genetics volume 43, pages 259–263 (2011)Cite this article

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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.

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Figure 1: Clinical and molecular genetic features of individuals with mutations in TTC19.
Figure 2: TTC19 subcellular localization.
Figure 3: Protein characterization in individuals with mutations in TTC19.
Figure 4: Structural analysis of TTC19 interactions.
Figure 5: Characterization of TTC19-null flies.

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Acknowledgements

We are grateful to S. Zanotti for technical support in preparing myoblast cultures and R. Saccon and D. Zanini for helping with the locomotor assays and bang tests. We thank M. Gatti, 'La Sapienza' University, Rome, Italy, for helping with analysis of spermatid development in D. melanogaster and A. Megighian for ERGs studies. The EuroBioBank and Telethon Network of Genetic Biobanks (GTB07001F grant to M. Mora) are also gratefully acknowledged for providing biological samples. This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, the Fondazione Telethon-Italy grant numbers GGP07019 and GPP10005, and grant RF-INN-2007-634163 of the Italian Ministry of Health to M. Zeviani and by grants of the Cariparo Foundation; the Ministry of Education and Research and Progetto Strategico Università di Padova 'Models of Mitochondrial Disease' to R.C.

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Author notes

  1. Daniele Ghezzi and Paola Arzuffi: These authors contributed equally to this work.

Authors and Affiliations

  1. Unit of Molecular Neurogenetics, The Foundation 'Carlo Besta' Institute of Neurology, Milan, Italy

    Daniele Ghezzi, Paola Arzuffi, Costanza Lamperti, Daria Diodato & Massimo Zeviani

  2. Department of Biology, Neurogenetics and Behaviour of Drosophila Lab, University of Padova, Padova, Italy

    Mauro Zordan, Caterina Da Re, Clara Benna & Rodolfo Costa

  3. Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico, Burlo Garofolo, University of Trieste, Trieste, Italy

    Pio D'Adamo

  4. Unit of Laboratory Medicine, The Foundation 'Carlo Besta' Institute of Neurology, Milan, Italy

    Caterina Mariotti

  5. Unit of Child Neurology, The Foundation 'Carlo Besta' Institute of Neurology, Milan, Italy

    Graziella Uziel

  6. Division of Physical Medicine and Rehabilitation, Public Health Hospital, Bassano del Grappa, Italy

    Cristina Smiderle

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  1. Daniele Ghezzi
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Contributions

D.G. and P.A. found TTC19 and characterized the mutations in human cells. C.L. performed the histological analysis of muscle biopsies. M. Zordan, C.D.R., C.B. and R.C. carried out the experiments in flies. C.M., G.U. and C.S. identified the subjects and carried out the clinical workout. P.D'A. performed linkage analysis. D.D. carried out the mutational screening on subjects 3 and 4 and the controls. M. Zeviani conceived the experimental planning and wrote the manuscript.

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Correspondence to Massimo Zeviani.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Figures 1–12 and Supplementary Tables 1–5 (PDF 6898 kb)

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Ghezzi, D., Arzuffi, P., Zordan, M. et al. Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies. Nat Genet 43, 259–263 (2011). https://doi.org/10.1038/ng.761

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