TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy

Article metrics


We carried out whole-genome homozygosity mapping, gene expression analysis and DNA sequencing in individuals with isolated mitochondrial ATP synthase deficiency and identified disease-causing mutations in TMEM70. Complementation of the cell lines of these individuals with wild-type TMEM70 restored biogenesis and metabolic function of the enzyme complex. Our results show that TMEM70 is involved in mitochondrial ATP synthase biogenesis in higher eukaryotes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Positional cloning of TMEM70.
Figure 2: TMEM70 complementation of ATP synthase deficiency.


  1. 1

    Collinson, I.R., Skehel, J.M., Fearnley, I.M., Runswick, M.J. & Walker, J.E. Biochemistry 35, 12640–12646 (1996).

  2. 2

    Ackerman, S.H. & Tzagoloff, A. Prog. Nucleic Acid Res. Mol. Biol. 80, 95–133 (2005).

  3. 3

    Pickova, A., Potocky, M. & Houstek, J. Proteins 59, 393–402 (2005).

  4. 4

    Wang, Z.G., White, P.S. & Ackerman, S.H. J. Biol. Chem. 276, 30773–30778 (2001).

  5. 5

    Zeng, X., Neupert, W. & Tzagoloff, A. Mol. Biol. Cell 18, 617–626 (2007).

  6. 6

    Houstek, J. et al. Biochim. Biophys. Acta 1757, 1400–1405 (2006).

  7. 7

    Schon, E.A., Santra, S., Pallotti, F. & Girvin, M.E. Semin. Cell Dev. Biol. 12, 441–448 (2001).

  8. 8

    Jonckheere, A. et al. J. Med. Genet. 45, 129–133 (2007).

  9. 9

    Houstek, J. et al. Hum. Mol. Genet. 8, 1967–1974 (1999).

  10. 10

    Sperl, W. et al. Neuromuscul. Disord. 16, 821–829 (2006).

  11. 11

    De Meirleir, L. et al. J. Med. Genet. 41, 120–124 (2004).

  12. 12

    Mayr, J.A. et al. Pediatr. Res. 55, 988–994 (2004).

  13. 13

    Cizkova, A. et al. BMC Genomics 9, 38 (2008).

  14. 14

    Calvo, S. et al. Nat. Genet. 38, 576–582 (2006).

Download references


This study was supported by grants from Ministry of Education of Czech Republic (1M6837805002, AV0Z 50110509, MSM0021620806, Kontakt 14/2006), GAČR (305/08/H037), OeNB 12568, Päd. Forschungsverein and PMU Salzburg (06/04/022). We thank R.Gallyová, Š.Rosipal, V.Smolka, A.Hlavatá, P.Freisinger, M.Huemer and O.Bodamer, who provided samples from affected individuals for this study, and D. Seelow for bioinformatic support.

Author information

A.C., H.Hartmannová and L.N. carried out DNA and gene expression analysis and TMEM70 cloning. V.S. and R.I. were responsible for genotyping, gene expression analysis and bioinformatics. J.A.M. carried out biochemical diagnosis and DNA analysis. A.W.K. did genotyping and homozygosity mapping. M.T. and H.Hansíková carried out biochemical diagnosis, cell culturing and transfections. V.H., J.P. and V.K. carried out transfections, complementation studies, ELFO/WB analysis and bioinformatics. M.V., Z.D. and K.H. were responsible for functional studies. T.H. and M.M. were responsible for family ascertainment and sample collection, and J.Z. and W.S. handled diagnosis and clinical characterization. S.K. and J.H. initiated and coordinated the study and wrote the manuscript.

Correspondence to Josef Houštěk or Stanislav Kmoch.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 1 and 2, Supplementary Methods (PDF 272 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading