A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4

Abstract

Translation of mitochondrial-specific DNA is required for proper mitochondrial function and energy production. For this purpose, an elaborate network of dedicated molecular machinery including initiation, elongation and termination factors exists. We describe a patient with an unusual phenotype and a novel homozygous missense variant in TUFM (c.344A>C; p.His115Pro), encoding mtDNA translation elongating factor Tu (EFTu). To date, only four patients have been reported with bi-allelic mutations in TUFM, leading to combined oxidative phosphorylation deficiency 4 (COXPD4) characterized by severe early-onset lactic acidosis and progressive fatal infantile encephalopathy. The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy. This warrants the inclusion of TUFM in differential diagnosis of metabolic cardiomyopathy. Cases that further refine genotype-phenotype associations and characterize the molecular basis of mitochondrial disorders allow clinicians to predict disease prognosis, greatly impacting patient care, as well as provide families with reproductive planning options.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1

References

  1. 1.

    Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: What is new and what challenges remain? Science. 2015;349:1494–9.

    CAS  Article  Google Scholar 

  2. 2.

    Koopman WJH, Willems PHGM, Smeitink JAM. Monogenic mitochondrial disorders. N Engl J Med. 2012;366:1132–41.

    CAS  Article  Google Scholar 

  3. 3.

    Pearce S, Nezich CL, Spinazzola A. Mitochondrial diseases: translation matters. Mol Cell Neurosci. 2013;55:1–12.

    CAS  Article  Google Scholar 

  4. 4.

    Brunel-Guitton C, Levtova A, Sasarman F. Mitochondrial diseases and cardiomyopathies. Can J Cardiol. 2015;31:1360–76.

    Article  Google Scholar 

  5. 5.

    Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S, Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901–13.

    CAS  Article  Google Scholar 

  6. 6.

    Ashkenazy H, Abadi S, Martz E, Chay O, Mayrose I, Pupko T, et al. ConSurf 2016: an improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Res. 2016;44(W1):W344–50.

    CAS  Article  Google Scholar 

  7. 7.

    Jeppesen MG, Navratil T, Spremulli LL, Nyborg J. Crystal structure of the bovine mitochondrial elongation factor Tu-Ts complex. J Biol Chem. 2005;280:5071–81.

    CAS  Article  Google Scholar 

  8. 8.

    Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014;42(W1):1–7.

    Article  Google Scholar 

  9. 9.

    Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER suite: protein structure and function prediction. Nat Methods. 2014;12:7–8.

    Article  Google Scholar 

  10. 10.

    Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12.

    CAS  Article  Google Scholar 

  11. 11.

    Shufaro Y, Lebovich M, Aizenman E, Miller C, Simon A, Laufer N, et al. Human granulosa luteal cell oxidative phosphorylation function is not affected by age or ovarian response. Fertil Steril. 2012;98:166–72.

    CAS  Article  Google Scholar 

  12. 12.

    Saada A, Shaag A, Elpeleg O. mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency. Mol Genet Metab. 2003;79:1–5.

    CAS  Article  Google Scholar 

  13. 13.

    Vossen RHAM, Buermans HPJ. Full-length mitochondrial-DNA sequencing on the PacBio RSII. Methods Mol Biol. 2017;1492:179–84.

    CAS  Article  Google Scholar 

  14. 14.

    Weissensteiner H, Forer L, Fuchsberger C, Schöpf B, Kloss-Brandstätter A, Specht G, et al. mtDNA-Server: next-generation sequencing data analysis of human mitochondrial DNA in the cloud. Nucleic Acids Res. 2016;44(W1):W64–9.

    CAS  Article  Google Scholar 

  15. 15.

    Fernandes V, Alshamali F, Alves M, Costa MD, Pereira JB, Silva NM, et al. The Arabian cradle: mitochondrial relicts of the first steps along the southern route out of Africa. Am J Hum Genet. 2012;90:347–55.

    CAS  Article  Google Scholar 

  16. 16.

    Burnett BJ, Altman RB, Ferrao R, Alejo JL, Kaur N, Kanji J, et al. Elongation factor Ts directly facilitates the formation and disassembly of the escherichia coli elongation factor Tu·GTP·aminoacyl-tRNA ternary complex. J Biol Chem. 2013;288:13917–28.

    CAS  Article  Google Scholar 

  17. 17.

    Smeitink JA, Elpeleg O, Antonicka H, Diepstra H, Saada A, Smits P, et al. Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs. Am J Hum Genet. 2006;79:869–77.

    CAS  Article  Google Scholar 

  18. 18.

    Valente L, Tiranti V, Marsano RM, Malfatti E, Fernandez-Vizarra E, Donnini C, et al. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am J Hum Genet. 2007;80:44–58.

    CAS  Article  Google Scholar 

  19. 19.

    Di Nottia M, Montanari A, Verrigni D, Oliva R, Torraco A, Fernandez-Vizarra E, et al. Novel mutation in mitochondrial elongation factor EF-Tu associated to dysplastic leukoencephalopathy and defective mitochondrial DNA translation. Biochim Biophys Acta. 2017;1863:961–7.

    Article  Google Scholar 

  20. 20.

    Kohda M, Tokuzawa Y, Kishita Y, Nyuzuki H, Moriyama Y, Mizuno Y, et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 2016;12:1–31.

    Article  Google Scholar 

  21. 21.

    Ahola S, Isohanni P, Euro L, Brilhante V, Palotie A, Pihko H, et al. Mitochondrial EFTs defects in juvenile-onset leigh disease, ataxia, neuropathy, and optic atrophy. Neurology. 2014;83:743–51.

    Article  Google Scholar 

  22. 22.

    Ravn K, Schönewolf-Greulich B, Hansen RM, Bohr AH, Duno M, Wibrand F, et al. Neonatal mitochondrial hepatoencephalopathy caused by novel GFM1 mutations. Mol Genet Metab Rep. 2015;3:5–10.

    CAS  Article  Google Scholar 

  23. 23.

    Antonicka H, Sasarman F, Kennaway NG, Shoubridge EA. The molecular basis for tissue specificity of the oxidative phosphorylation deficiencies in patients with mutations in the mitochondrial translation factor EFG1. Hum Mol Genet. 2006;15:1835–46.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the patient’s parents for participating in this study. We are grateful to the medical and nursing staff at the pediatric intensive care unit (PICU), Ruth Rappaport Children’s Hospital, Rambam Health Care Campus for their dedicated work and patient care. Corinne Alban, Department of Genetic and metabolic Diseases Hadassah Medical Center, is acknowledged for technical assistance.

Author information

Affiliations

Authors

Consortia

Corresponding author

Correspondence to Hagit Baris Feldman.

Ethics declarations

Conflict of interest

CG-J, SEW, JDO, and ARS are full-time employees of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receive stock options as part of compensation. The remaining authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hershkovitz, T., Kurolap, A., Gonzaga-Jauregui, C. et al. A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4. J Hum Genet 64, 589–595 (2019). https://doi.org/10.1038/s10038-019-0592-6

Download citation

Further reading

Search