Skip to main content
NCBI home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2004 May;41(5):342–349. doi: 10.1136/jmg.2003.016048

Variable penetrance of a familial progressive necrotising encephalopathy due to a novel tRNAIle homoplasmic mutation in the mitochondrial genome

A Limongelli 1, J Schaefer 1, S Jackson 1, F Invernizzi 1, Y Kirino 1, T Suzuki 1, H Reichmann 1, M Zeviani 1
PMCID: PMC1735786  PMID: 15121771

Abstract

Introduction: We present a family comprising a clinically normal mother and two daughters, each with severe encephalopathy with onset in late childhood. A third daughter had died previously of an earlier onset but neuropathologically similar disease.

Methods: Sequence analysis of the entire mtDNA was carried out in muscle, fibroblasts, and lymphocytes of the affected daughters and unaffected mother. Biochemical analysis of individual respiratory chain enzymes was performed on the same tissues, and on several transmitochondrial cybrid clones containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA.

Results: Genetic analyses revealed in both daughters and mother the presence of a novel mutation in the tRNAIle gene of mtDNA, which was homoplasmic in fibroblasts, lymphocytes, and skeletal muscle of the two patients. It was also homoplasmic in fibroblast and skeletal muscle samples of the mother, and approximately 97% heteroplasmic in her lymphocytes. Combined defects of complexes I and IV of the mitochondrial respiratory chain were found not only in fibroblasts of the two probands, but surprisingly also in those of their clinically unaffected mother. The respiratory chain defect segregated in transmitochondrial cybrids containing the nucleus of a 143B.206 osteosarcoma cell line and the mutant mtDNA, indicating that the latter was responsible for the biochemical phenotype.

Discussion: Our results support the concept that homoplasmic mutations in tRNA genes can be responsible for mitochondrial disorders characterised by extremely variable penetrance. Albeit still unexplained, this phenomenon has important consequences in the nosological characterisation, clinical management, and genetic counselling of mitochondrial disorders.

Full Text

The Full Text of this article is available as a PDF (631.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  2. Chinnery P. F., Johnson M. A., Wardell T. M., Singh-Kler R., Hayes C., Brown D. T., Taylor R. W., Bindoff L. A., Turnbull D. M. The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol. 2000 Aug;48(2):188–193. [PubMed] [Google Scholar]
  3. Chinnery P. F., Turnbull D. M. Mitochondrial medicine. QJM. 1997 Nov;90(11):657–667. doi: 10.1093/qjmed/90.11.657. [DOI] [PubMed] [Google Scholar]
  4. Chomyn A. In vivo labeling and analysis of human mitochondrial translation products. Methods Enzymol. 1996;264:197–211. doi: 10.1016/s0076-6879(96)64020-8. [DOI] [PubMed] [Google Scholar]
  5. DiMauro S., De Vivo D. C. Genetic heterogeneity in Leigh syndrome. Ann Neurol. 1996 Jul;40(1):5–7. doi: 10.1002/ana.410400104. [DOI] [PubMed] [Google Scholar]
  6. Estivill X., Govea N., Barceló E., Badenas C., Romero E., Moral L., Scozzri R., D'Urbano L., Zeviani M., Torroni A. Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment of aminoglycosides. Am J Hum Genet. 1998 Jan;62(1):27–35. doi: 10.1086/301676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Farina Laura, Chiapparini Luisa, Uziel Graziella, Bugiani Marianna, Zeviani Massimo, Savoiardo Mario. MR findings in Leigh syndrome with COX deficiency and SURF-1 mutations. AJNR Am J Neuroradiol. 2002 Aug;23(7):1095–1100. [PMC free article] [PubMed] [Google Scholar]
  8. Hutchin T. P., Cortopassi G. A. Mitochondrial defects and hearing loss. Cell Mol Life Sci. 2000 Dec;57(13-14):1927–1937. doi: 10.1007/PL00000673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. King M. P., Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science. 1989 Oct 27;246(4929):500–503. doi: 10.1126/science.2814477. [DOI] [PubMed] [Google Scholar]
  10. LEIGH D. Subacute necrotizing encephalomyelopathy in an infant. J Neurol Neurosurg Psychiatry. 1951 Aug;14(3):216–221. doi: 10.1136/jnnp.14.3.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  12. Maassen J. Antonie. Mitochondrial diabetes: pathophysiology, clinical presentation, and genetic analysis. Am J Med Genet. 2002 May 30;115(1):66–70. doi: 10.1002/ajmg.10346. [DOI] [PubMed] [Google Scholar]
  13. Mariotti C., Tiranti V., Carrara F., Dallapiccola B., DiDonato S., Zeviani M. Defective respiratory capacity and mitochondrial protein synthesis in transformant cybrids harboring the tRNA(Leu(UUR)) mutation associated with maternally inherited myopathy and cardiomyopathy. J Clin Invest. 1994 Mar;93(3):1102–1107. doi: 10.1172/JCI117061. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McFarland Robert, Clark Kim M., Morris Andrew A. M., Taylor Robert W., Macphail Sheila, Lightowlers Robert N., Turnbull Douglass M. Multiple neonatal deaths due to a homoplasmic mitochondrial DNA mutation. Nat Genet. 2002 Jan 22;30(2):145–146. doi: 10.1038/ng819. [DOI] [PubMed] [Google Scholar]
  15. Munaro M., Tiranti V., Sandonà D., Lamantea E., Uziel G., Bisson R., Zeviani M. A single cell complementation class is common to several cases of cytochrome c oxidase-defective Leigh's syndrome. Hum Mol Genet. 1997 Feb;6(2):221–228. doi: 10.1093/hmg/6.2.221. [DOI] [PubMed] [Google Scholar]
  16. Nijtmans L. G., Taanman J. W., Muijsers A. O., Speijer D., Van den Bogert C. Assembly of cytochrome-c oxidase in cultured human cells. Eur J Biochem. 1998 Jun 1;254(2):389–394. doi: 10.1046/j.1432-1327.1998.2540389.x. [DOI] [PubMed] [Google Scholar]
  17. Rahman S., Blok R. B., Dahl H. H., Danks D. M., Kirby D. M., Chow C. W., Christodoulou J., Thorburn D. R. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996 Mar;39(3):343–351. doi: 10.1002/ana.410390311. [DOI] [PubMed] [Google Scholar]
  18. Sasarman Florin, Karpati George, Shoubridge Eric A. Nuclear genetic control of mitochondrial translation in skeletal muscle revealed in patients with mitochondrial myopathy. Hum Mol Genet. 2002 Jul 1;11(14):1669–1681. doi: 10.1093/hmg/11.14.1669. [DOI] [PubMed] [Google Scholar]
  19. Schägger H., von Jagow G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal Biochem. 1991 Dec;199(2):223–231. doi: 10.1016/0003-2697(91)90094-a. [DOI] [PubMed] [Google Scholar]
  20. Sciacco M., Bonilla E. Cytochemistry and immunocytochemistry of mitochondria in tissue sections. Methods Enzymol. 1996;264:509–521. doi: 10.1016/s0076-6879(96)64045-2. [DOI] [PubMed] [Google Scholar]
  21. Taanman J. W., Burton M. D., Marusich M. F., Kennaway N. G., Capaldi R. A. Subunit specific monoclonal antibodies show different steady-state levels of various cytochrome-c oxidase subunits in chronic progressive external ophthalmoplegia. Biochim Biophys Acta. 1996 Apr 12;1315(3):199–207. doi: 10.1016/0925-4439(95)00127-1. [DOI] [PubMed] [Google Scholar]
  22. Taylor Robert W., Giordano Carla, Davidson Mercy M., d'Amati Giulia, Bain Hugh, Hayes Christine M., Leonard Helen, Barron Martin J., Casali Carlo, Santorelli Filippo M. A homoplasmic mitochondrial transfer ribonucleic acid mutation as a cause of maternally inherited hypertrophic cardiomyopathy. J Am Coll Cardiol. 2003 May 21;41(10):1786–1796. doi: 10.1016/s0735-1097(03)00300-0. [DOI] [PubMed] [Google Scholar]
  23. Tiranti V., Corona P., Greco M., Taanman J. W., Carrara F., Lamantea E., Nijtmans L., Uziel G., Zeviani M. A novel frameshift mutation of the mtDNA COIII gene leads to impaired assembly of cytochrome c oxidase in a patient affected by Leigh-like syndrome. Hum Mol Genet. 2000 Nov 1;9(18):2733–2742. doi: 10.1093/hmg/9.18.2733. [DOI] [PubMed] [Google Scholar]
  24. Tiranti V., Galimberti C., Nijtmans L., Bovolenta S., Perini M. P., Zeviani M. Characterization of SURF-1 expression and Surf-1p function in normal and disease conditions. Hum Mol Genet. 1999 Dec;8(13):2533–2540. doi: 10.1093/hmg/8.13.2533. [DOI] [PubMed] [Google Scholar]
  25. Torroni A., Rengo C., Guida V., Cruciani F., Sellitto D., Coppa A., Calderon F. L., Simionati B., Valle G., Richards M. Do the four clades of the mtDNA haplogroup L2 evolve at different rates? Am J Hum Genet. 2001 Oct 10;69(6):1348–1356. doi: 10.1086/324511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vu Tuan H., Hirano Michio, DiMauro Salvatore. Mitochondrial diseases. Neurol Clin. 2002 Aug;20(3):809-39, vii-viii. doi: 10.1016/s0733-8619(01)00017-2. [DOI] [PubMed] [Google Scholar]
  27. Y-W-Man P., Turnbull D. M., Chinnery P. F. Leber hereditary optic neuropathy. J Med Genet. 2002 Mar;39(3):162–169. doi: 10.1136/jmg.39.3.162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Zeviani M., Moraes C. T., DiMauro S., Nakase H., Bonilla E., Schon E. A., Rowland L. P. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology. 1988 Sep;38(9):1339–1346. doi: 10.1212/wnl.38.9.1339. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES