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Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype

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Abstract

Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.

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References

  1. Coenen MJ, Antonicka H, Ugalde C, Sasarman F, Rossi R, Heister JG, Newbold RF, Trijbels FJ, van den Heuvel LP, Shoubridge EA, Smeitink JA (2004) Mutant mitochondrial elongation factor G1 and combined oxidative phosphorylation deficiency. N Engl J Med 351(20):2080–2086

    Article  CAS  PubMed  Google Scholar 

  2. Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS, Baruffini E, Melchionda L, Mariotti C, Strom TM, Meitinger T, Prokisch H, Chapman K, Colley A, Rocha H, Ounap K, Schiffmann R, Salsano E, Savoiardo M, Hamilton EM, Abbink TE, Wolf NI, Ferrero I, Lamperti C, Zeviani M, Vanderver A, Ghezzi D, van der Knaap MS (2014) Novel (ovario) leukodystrophy related to AARS2 mutations. Neurology 82(23):2063–2071. doi:10.1212/WNL.0000000000000497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Diodato D, Melchionda L, Haack TB, Dallabona C, Baruffini E, Donnini C, Granata T, Ragona F, Balestri P, Margollicci M, Lamantea E, Nasca A, Powell CA, Minczuk M, Strom TM, Meitinger T, Prokisch H, Lamperti C, Zeviani M, Ghezzi D (2014) VARS2 and TARS2 mutations in patients with mitochondrial encephalomyopathies. Hum Mutat 35(8):983–989. doi:10.1002/humu.22590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Edvardson S, Shaag A, Kolesnikova O, Gomori JM, Tarassov I, Einbinder T, Saada A, Elpeleg O (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81(4):857–862. doi:10.1086/521227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Scheper GC, van der Klok T, van Andel RJ, van Berkel CG, Sissler M, Smet J, Muravina TI, Serkov SV, Uziel G, Bugiani M, Schiffmann R, Krageloh-Mann I, Smeitink JA, Florentz C, Van Coster R, Pronk JC, van der Knaap MS (2007) Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet 39(4):534–539. doi:10.1038/ng2013

    Article  CAS  PubMed  Google Scholar 

  6. Smits P, Smeitink J, van den Heuvel L (2010) Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010:737385. doi:10.1155/2010/737385

    Article  PubMed  PubMed Central  Google Scholar 

  7. Steenweg ME, Ghezzi D, Haack T, Abbink TE, Martinelli D, van Berkel CG, Bley A, Diogo L, Grillo E, Te Water Naude J, Strom TM, Bertini E, Prokisch H, van der Knaap MS, Zeviani M (2012) Leukoencephalopathy with thalamus and brainstem involvement and high lactate ‘LTBL’ caused by EARS2 mutations. Brain J Neurol 135(Pt 5):1387–1394. doi:10.1093/brain/aws070

    Article  Google Scholar 

  8. Takeuchi N, Kawakami M, Omori A, Ueda T, Spremulli LL, Watanabe K (1998) Mammalian mitochondrial methionyl-tRNA transformylase from bovine liver. Purification, characterization, and gene structure. J Biol Chem 273(24):15085–15090

    Article  CAS  PubMed  Google Scholar 

  9. Tucker EJ, Hershman SG, Kohrer C, Belcher-Timme CA, Patel J, Goldberger OA, Christodoulou J, Silberstein JM, McKenzie M, Ryan MT, Compton AG, Jaffe JD, Carr SA, Calvo SE, RajBhandary UL, Thorburn DR, Mootha VK (2011) Mutations in MTFMT underlie a human disorder of formylation causing impaired mitochondrial translation. Cell Metab 14(3):428–434. doi:10.1016/j.cmet.2011.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Haack TB, Haberberger B, Frisch EM, Wieland T, Iuso A, Gorza M, Strecker V, Graf E, Mayr JA, Herberg U, Hennermann JB, Klopstock T, Kuhn KA, Ahting U, Sperl W, Wilichowski E, Hoffmann GF, Tesarova M, Hansikova H, Zeman J, Plecko B, Zeviani M, Wittig I, Strom TM, Schuelke M, Freisinger P, Meitinger T, Prokisch H (2012) Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing. J Med Genet 49(4):277–283. doi:10.1136/jmedgenet-2012-100846

    Article  CAS  PubMed  Google Scholar 

  11. Neeve VC, Pyle A, Boczonadi V, Gomez-Duran A, Griffin H, Santibanez-Koref M, Gaiser U, Bauer P, Tzschach A, Chinnery PF, Horvath R (2013) Clinical and functional characterisation of the combined respiratory chain defect in two sisters due to autosomal recessive mutations in MTFMT. Mitochondrion 13(6):743–748. doi:10.1016/j.mito.2013.03.002

  12. Haack TB, Gorza M, Danhauser K, Mayr JA, Haberberger B, Wieland T, Kremer L, Strecker V, Graf E, Memari Y, Ahting U, Kopajtich R, Wortmann SB, Rodenburg RJ, Kotzaeridou U, Hoffmann GF, Sperl W, Wittig I, Wilichowski E, Schottmann G, Schuelke M, Plecko B, Stephani U, Strom TM, Meitinger T, Prokisch H, Freisinger P (2014) Phenotypic spectrum of eleven patients and five novel MTFMT mutations identified by exome sequencing and candidate gene screening. Mol Genet Metab 111(3):342–352. doi:10.1016/j.ymgme.2013.12.010

    Article  CAS  PubMed  Google Scholar 

  13. Hinttala R, Sasarman F, Nishimura T, Antonicka H, Brunel-Guitton C, Schwartzentruber J, Fahiminiya S, Majewski J, Faubert D, Ostergaard E, Smeitink JA, Shoubridge EA (2015) An N-terminal formyl methionine on COX 1 is required for the assembly of cytochrome c oxidase. Hum Mol Genet 24(14):4103–4113. doi:10.1093/hmg/ddv149

  14. Pena JA, Lotze T, Yang Y, Umana L, Walkiewicz M, Hunter JV, Scaglia F (2016) Methionyl-tRNA formyltransferase (MTFMT) deficiency mimicking acquired demyelinating disease. J Child Neurol 31(2):215–219. doi:10.1177/0883073815587946

    Article  PubMed  Google Scholar 

  15. Kemp JP, Smith PM, Pyle A, Neeve VC, Tuppen HA, Schara U, Talim B, Topaloglu H, Holinski-Feder E, Abicht A, Czermin B, Lochmuller H, McFarland R, Chinnery PF, Chrzanowska-Lightowlers ZM, Lightowlers RN, Taylor RW, Horvath R (2011) Nuclear factors involved in mitochondrial translation cause a subgroup of combined respiratory chain deficiency. Brain J Neurol 134(Pt 1):183–195. doi:10.1093/brain/awq320

    Article  Google Scholar 

  16. Kumar P, Henikoff S, Ng PC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protocols 4(8):1073–1081

    Article  CAS  PubMed  Google Scholar 

  17. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249. doi:10.1038/nmeth0410-248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sasarman F, Shoubridge EA (2012) Radioactive labeling of mitochondrial translation products in cultured cells. Methods Mol Biol 837:207–217. doi:10.1007/978-1-61779-504-6_14

    Article  CAS  PubMed  Google Scholar 

  19. Sinha A, Kohrer C, Weber MH, Masuda I, Mootha VK, Hou YM, RajBhandary UL (2014) Biochemical characterization of pathogenic mutations in human mitochondrial methionyl-tRNA formyltransferase. J Biol Chem 289(47):32729–32741. doi:10.1074/jbc.M114.610626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Procaccio V, Wallace DC (2004) Late-onset Leigh syndrome in a patient with mitochondrial complex I NDUFS8 mutations. Neurology 62(10):1899–1901

  21. Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, Lochmuller H, Chevrette M, Kaufman BA, Horvath R, Shoubridge EA (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 41(7):833–837 http://www.nature.com/ng/journal/v41/n7/suppinfo/ng.390_S1.html

    Article  CAS  PubMed  Google Scholar 

  22. Nafisinia M, Guo Y, Dang X, Li J, Chen Y, Zhang J, Lake NJ, Gold WA, Riley LG, Thorburn DR, Keating B, Xu X, Hakonarson H, Christodoulou J (2016) Whole exome sequencing identifies the genetic basis of late-onset Leigh syndrome in a patient with MRI but little biochemical evidence of a mitochondrial disorder. JIMD Rep. doi:10.1007/8904_2016_541

  23. Seeger J, Schrank B, Pyle A, Stucka R, Lörcher U, Müller-Zierman S, Abicht A, Czermin B, Holinski-Feder E, Lochmüller H, Horvath R (2010). Clinical and neuropathological findings in patients with TACO1 mutations. Neuromuscular Disorders 20(11):720–724. doi:10.1016/j.nmd.2010.06.017

  24. Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, Lochmuller H, Chevrette M, Kaufman BA, Horvath R, Shoubridge EA (2009) Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 41(7):833–837. doi:10.1038/ng.390

    Article  CAS  PubMed  Google Scholar 

  25. Barcella V, Rocca MA, Bianchi-Marzoli S, Milesi J, Melzi L, Falini A, Pierro L, Filippi M (2010) Evidence for retrochiasmatic tissue loss in Leber’s hereditary optic neuropathy. Hum Brain Mapp 31(12):1900–1906. doi:10.1002/hbm.20985

    Article  PubMed  Google Scholar 

  26. Ogawa S, Takemura H, Horiguchi H, Terao M, Haji T, Pestilli F, Yeatman JD, Tsuneoka H, Wandell BA, Masuda Y (2014) White matter consequences of retinal receptor and ganglion cell DamageVisual white matter damage following retinal disease. Invest Ophthalmol Vis Sci 55(10):6976–6986. doi:10.1167/iovs.14-14737

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to the affected patient and her family. RLP is the recipient of a doctoral award from the Fonds de Recherche du Québec—Santé (FRQS) and has been supported by the Fondation Monaco. MT is a recipient of the postdoctoral fellowship from the Canadian Institute of Health Research (CIHR). This work was supported by the Canadian Foundation of Radiologists, the Care4Rare Canada Consortium (steering committee: Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), and David Dyment (University of Ottawa)) and funded in part by Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and the Children’s Hospital of Eastern Ontario Foundation and an operating grant from the CIHR (MT15460) to EAS.

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Correspondence to Eric A. Shoubridge.

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The Institutional Review Board of our institution approved the research study, and the subject reported here gave her consent to participate in the study.

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Supplementary Figure 1.

Fundus photographs showing the progressive atrophy of the left optic nerve (A) in 2010 and (B) at the last clinical follow up in 2014. (GIF 250 kb)

High Resolution Image (TIFF 32.7 kb)

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La Piana, R., Weraarpachai, W., Ospina, L.H. et al. Identification and functional characterization of a novel MTFMT mutation associated with selective vulnerability of the visual pathway and a mild neurological phenotype. Neurogenetics 18, 97–103 (2017). https://doi.org/10.1007/s10048-016-0506-0

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  • DOI: https://doi.org/10.1007/s10048-016-0506-0

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