Abstract
The distributrion of the causal 8344A→G mtDNA mutation has been examined in six tissues of a patient with myoclonic epilepsy with ragged red fibers (MERRF), to study the developmental genetics of this type of mitochondrial disorder, and to determine the pathophysiological importance of the mtDNA heteroplasmy generally observed in such patients. Heteroplasmy of the mtDNA was observed in all six tissues (cerebellum, cerebrum, pancreas, liver, muscle, and heart) suggesting that, whereas the mtDNA mutation is relatively new, the mutated population must have existed before the formation of the three primary embryonic layers. The tissue distribution reveals significant variations in the ratio between the mutated and the normal mtDNA species, indicating the randomness of mtDNA segregation during developmental cell division and differentiation events. The result suggests the existence of tissue-specific nuclear factor(s) that determines the expression of the 8344A→G mutation in various tissues; in MERRF syndrome, expression is mainly in the central nervous system.
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Byrne E, Trounce I, Marzuki S, Dennett X, Berkovic SF, Davis F, Ozawa T, et al (1990) Functional respiratory chain studies in mitochondrial cytopathies. Support for mitochondrial DNA heteroplasmy in myoclonus epilepsy and ragged red fibers (MERRF) syndrome. Acta Neuropathol 81:318–323
Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T (1980) Myoclonus epilepsy associated with ragged red fibres (mitochondrial abnormalities): disease entity or a syndrome? J Neurol Sci 47:117–133
Goto Y, Nonaka I, Horai S (1990) A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348:651–653
Kobayashi Y, Momoi MY, Tominaga K, Momoi T, Nihei K, Yanagisawa M, Kagawa Y, Ohta S (1990) A point mutation in the mitochondrial tRNALeu(UUR) gene in MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). Biochem Biophys Res Commun 173:816–822
Lertrit P, Noer AS, Jean-Francois MJB, Kapsa R, Dennett X, Thyagarajan D, Lethlean K, Byrne B, Marzuki S (1992) A new disease-related mutation for mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS) syndrome afects the ND4 subunit of the respriatory complex I. Am J Hum Genet (in press)
Lestienne P, Ponsot G (1988) Kearns Sayre syndrome with muscle mitochondrial DNA deletion. Lancet I:885
Moreas CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, et al (1989) Mitochondrial DNA deletions in progressive external opthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320:1293–1299
Noer AS, Sudoyo H, Lertrit P, Thyagarajan D, Utthanaphol P, Kapsa R, Byrne E, Marzuki S (1991) A tRNALys mutation in the mtDNA is the causal genetic lesion underlying myoclonic epilepsy and ragged red fibre (MERRF) syndrome. Am J Hum Genet 49:715–722
Noer AS, Berkovic SF, Kapsa RMI, Kalnins RM, Byrne E, Marzuki S (1992) Developmental genetics of the partially deleted mtDNA observed in mitochondrial oculomyopathy. Biochim Biophys Acta (in press)
Obermaier-Kusser B, Muller-Hocker J, Nelson I, Lestienne P, Enter C, Riedele T, Gerbitz K-D (1990) Different copy numbers of apparently identically deleted mitochondrial DNA in tissues from a patient with Kearn-Sayre syndrome detected by PCR. Biochem Biophys Res Commun 169:1007–1015
Ponzetto C, Bresolin N, Bordoni A, Moggio M, Meola G, Bet L, Prelle A, Scarlato G (1990) Kearn-Sayre syndrome: different amounts of deleted mitochondrial DNA are present in several autoptic tissues. J Neurol Sci 96:207–210
Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. 2nd edn. Cold Spring Harbor Laboratory. Cold Spring Harbor, NY
Shanske S, Moreas CT, Lombes A, Miranda AF, Bonilla E, Lewis P, Whalan MA, et al (1990) Widespread tissue distribution of mitochondrial DNA deletions in Kearns-Sayre syndrome. Neurology 40:24–28
Shoffner JM, Lott MT, Lezza AMS, Seibel P, Ballinger SW, Wallace DC (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNAIys mutation. Cell 61:931–937
Tanaka M, Ino H, Ohno K, Ohbayashi T, Ikebe S, Sano T, Ichiki T, et al (1991) Mitochondrial DNA mutations in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) Biochem Biophys Res Commun 174:861–868
Vilkki J, Ott J, Savontaus M-L, Aula P, Nikoskelainen EF (1991) Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7. Am J Hum Genet 48:486–491
Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas II LJ, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427–1430
Zeviani M, Gellera C, Pannacci M, Uziel G, Prelle A, Servidei S, DiDonato S (1990) Tissue distribution and transmission of mitochondrial DNA deletions in mitochondrial myopathies. nn Neurol 28:94–97
Zeviani M, Amati P, Bresolin N, Antozzi C, Piccolo G, Toscano A, DiDonato S (1991) Rapid detection of the A→G(8344) mutaion of mtDNA in Italian families with myoclonus epilepsy and ragged red fibers (MERRF) Am J Hum Genet 48:203–210
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Lertrit, P., Noer, A.S., Byrne, E. et al. Tissue segregation of a heteroplasmic mtDNA mutation in MERRF (Myoclonic epilepsy with ragged red fibers) encephalomyopathy. Hum Genet 90, 251–254 (1992). https://doi.org/10.1007/BF00220072
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DOI: https://doi.org/10.1007/BF00220072