Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA

Abstract

We studied 22 subjects carrying the A3243G point mutation of human mitochondrial DNA (mtDNA). In 14 cases the clinical phenotype was characterized by mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), while 8 patients had chronic progressive external ophthalmoplegia (CPEO). The proportion of A3243G heteroplasmy in muscle was determined by two methods: densitometry on a diagnostic restriction-fragment length polymorphism and solid-phase mini-sequencing. We found a highly significant inverse correlation between the percentage of A3243G mutation and the specific activity of complex 1, the respiratory complex with the highest number of mtDNA-encoded subunits, suggesting a direct effect of the mutation on mtDNA translation. No correlation was observed between the percentage of mutated mtDNA and the presence or absence of specific clinical features, such as stroke, ophthalmoplegia and diabetes mellitus. However, in the MELAS group the percentage of mutated mtDNA molecules was strongly correlated with the age of onset, while no such correlation was found in the CPEO group, suggesting a different time-dependent evolution of the mutation in the two groups. Finally, in contrast with other mtDNA mutations associated with ragged-red fibres (RRF), in both MELAS3243 and CPE03243 we observed a high proportion of RRF that were positive to the histochemical reaction to cytochromec oxidase, a morphological feature that seems to be specific for the neuromuscular phenotypes associated with mutations affecting the tRNALeu(UUR) gene.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Bindoff LA, Howell N, Poulton J, McCullough DA, Morten KJ, Lightowlers RN, Turnbull DM, Weber K (1993) Abnormal RNA processing associated with a novel tRNA mutation in mitochondrial DNA. J Biol Chem 268: 19559–19564

  2. 2.

    Chomyn A, Martinuzzi A, Yoneda M, Daga A, Hurko O, Johns D, Lai ST, Nonaka I, Angelini C, Attardi G (1992) MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc Natl Acad Sci USA 89:4221–4225

  3. 3.

    Ciafaloni E, Ricci E, Shanske S, Moraes CT, Silvestri G, Hirano M, Simonetti S, Angelini C, Donati A, Garcia C, Martinuzzi A, Mosewich R, Servidei S, Zammarchi E, Bonilla E, De Vivo DC, Rowland LP, Schon AE, Di Mauro S (1992) MELAS: clinical features, biochemistry, and molecular genetics. Ann Neurol 31:391–398

  4. 4.

    Darley-Usmar VM, Rickwood D, Wilson MT (eds) (1987) Mitochondria, a practical approach. IRL Press, Oxford

  5. 5.

    Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNALLeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653

  6. 6.

    Goto Y, Nonaka I, Horai S (1991) A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim Biophys Acta 1097:238–240

  7. 7.

    Goto Y, Horai S, Matsuoka T, Koga Y, Nihei K, Kobayashi M, Nonaka I (1992) Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): a correlative study of the clinical features and mitochondrial DNA mutation. Neurology 42:545–550

  8. 8.

    Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE (1991) Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet 337:1311–1313

  9. 9.

    Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA (1990) A new mitochondrial disease associated with mitochondrial heteroplasmy. Am J Hum Genet 46:428–433

  10. 10.

    Kadowaki T, Kadowaki H, Mori Y, Tobe K, Sakuta R, Suzuki Y, Tanabe Y, Sakura H, Awata T, Goto Y, Hayakawa T, Matsuoka K, Kawamori R, Kamada T, Horai S, Nonaka I, Hagura R, Akanuma Y, Yazaki Y (1994) A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med 330:962–968

  11. 11.

    King MP, Koga Y, Davidson M, Schon EA (1992) Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes. Mol Cell Biol 12:480–490

  12. 12.

    Macmillan C, Lach B, Shoubridge EA (1993) Variable distribution of mutant mitochondrial DNAs (tRNALeu[3243]) in tissues of symptomatic relatives with MELAS: the role of mitotic segregation. Neurology 43:1586–1590

  13. 13.

    Moraes CT, Ciacci F, Bonilla E, Jansen C, Hirano M, Rao N, Lovelace RE, Rowland LP, Schon EA, Di Mauro S (1993) Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is tRNALeu(UUR) gene an etiologic hot spot? J Clin Invest 92:2906–2915

  14. 14.

    Moraes CT, Ciacci F, Silvestri G, Shanske S, Sciacco M, Hirano M, Schon EA, Bonilla E, Di Mauro S (1993) Atypical clinical presentations associated with the MELAS mutation at position 3243 of human mitochondrial DNA. Neuromusc Disord 3:43–50

  15. 15.

    Petruzzella V, Moraes CT, Sano MC, Bonila E, Di Mauro S, Schon EA (1994) Extremely high levels of mutant mtDNA co-localize with cytochrome c oxidase-negative ragged-red fibres in patients harboring a point mutation at nt 3243. Hum Mol Genet 3:449–454

  16. 16.

    Reardon W, Ross RJM, Sweeney MG, Luxon LM, Pembrey ME, Harding AE, Trembath RC (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340:1376–1379

  17. 17.

    Santorelli FM, Shanske S, Macaya A, De Vivo DC, Di Mauro S (1993) The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh syn drome. Ann Neurol 34:827–834

  18. 18.

    Sciacco M, Bonilla E, Schon EA, Di Mauro S, Moraes CT (1994) Distribution of wild type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibres from patients with mitochondrial myopathy. Hum Mol Genet 3:13–19

  19. 19.

    Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC (1990) Myoclonic epilepsy and raggedred fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61:931–937

  20. 20.

    Silvestri G, Moraes CT, Shanske S, Oh SJ, Di Mauro S (1992) A new mtDNA mutation in the tRNAsLys gene associated with myoclonic epilepsy and ragged-red fibres (MERRF). Am J Hum Genet 51:1213–1217

  21. 21.

    Suomalainen A, Majander A, Pihko H, Peltonen L, Syvanen AC (1993) Quantification of the tRNA3243Leu point mutation of mitochondrial DNA in MELAS patients and its effects on mitochondrial transcription. Hum Mol Genet 2:525–534

  22. 22.

    Tatuch Y, Christodoulou J, Feigenbaum A, Clarke JTR, Wherret J, Smith C, Rudd N, Petrova-Benedict P, Robinson BH (1992) Heteroplasmy mtDNA mutation (T→G) at 8993 can cause Leigh disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 50:852–858

  23. 23.

    Van den Ouweland IMW, Lemkes HHPJ, Ruitenbeek W, Sandkuijl LA, Vijlder MF de, Struyvenberg PAA, Kamp JJP van de, Maassen JA (1992) Mutation in mitochondrial tRNA Leu(UUR) gene in a large pedigree with maternally trasmitted type 11 diabetes mellitus and deafness. Nature Genet 1:368–371

  24. 24.

    Zeviani M, Antozzi C (1992) Defects of mitochondrial DNA. Brain Pathol 2:121–132

  25. 25.

    Zeviani M, Moraes T, Di Mauro S, Nakase H, Bonilla E, Schon EA, Rowland LP (1988) Deletions of mitochonrial DNA in Kearns-Sayre syndrome. Neurology 38:1339–1346

  26. 26.

    Zeviani M, Muntoni F, Savarese N, Serra G, Tiranti V, Carrara F, Mariotti C, Di Donato S (1993) A MERRF/ MELAS overlap syndrome associated with a new point mutation in the mitochondrial DNA tRNALys gene. Eur J Hum Genet 1:80–87

Download references

Author information

Correspondence to Massimo Zeviani.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mariotti, C., Savarese, N., Suomalainen, A. et al. Genotype to phenotype correlations in mitochondrial encephalomyopathies associated with the A3243G mutation of mitochondrial DNA. J Neurol 242, 304–312 (1995). https://doi.org/10.1007/BF00878873

Download citation

Key words

  • Mitochondrial encephalomyopathy
  • Chronic progressive external ophthalmoplegia
  • Lactic acidosis
  • Stroke-like episodes
  • Ragged-red fibres