A TRNA(Lys) Mutation in the MtDNA is the Causal Genetic Lesion Underlying Myoclonic Epilepsy and Ragged-red Fiber (MERRF) Syndrome

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1991 Oct 1

PMID 1910259

Citations 27

Authors

A S Noer

H Sudoyo

P Lertrit

D Thyagarajan

P Utthanaphol

R Kapsa

E Byrne

S Marzuki

Affiliations

Soon will be listed here.

Abstract

Skeletal muscle mtDNA of three patients with mitochondrial encephalomyopathy, characterized clinically by myoclonic epilepsy and ragged-red fiber (MERRF) syndrome, has been sequenced to determine the underlying molecular defect(s). An A-to-G substitution of nt 8344 in the tRNA(Lys) gene, a substitution suggested to be associated with MERRF encephalomyopathy, was detected in these patients. Abnormal patterns of mitochondrial translation products were observed in the skeletal muscle of patients, consistent with the expected consequential defect in protein synthesis. The genealogical studies of the three patients, as well as mtDNA from one published MERRF patient and from nine other normal and disease controls, revealed that the tRNA(Lys) mutations in the MERRF patients have arisen independently. These observations provided evidence that the base substitution is a causal mutation for MERRF.

Citing Articles

RNA modifications in physiology and disease: towards clinical applications.

Delaunay S, Helm M, Frye M Nat Rev Genet. 2023; 25(2):104-122.

PMID: 37714958 DOI: 10.1038/s41576-023-00645-2.

The molecular pathology of pathogenic mitochondrial tRNA variants.

Richter U, McFarland R, Taylor R, Pickett S FEBS Lett. 2021; 595(8):1003-1024.

PMID: 33513266 PMC: 8600956. DOI: 10.1002/1873-3468.14049.

Progress in the molecular mechanisms of genetic epilepsies using patient-induced pluripotent stem cells.

Zhou R, Jiang G, Tian X, Wang X Epilepsia Open. 2018; 3(3):331-339.

PMID: 30187003 PMC: 6119748. DOI: 10.1002/epi4.12238.

Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury.

Rodriguez A, Nakhle J, Griessinger E, Vignais M Cell Cycle. 2018; 17(6):712-721.

PMID: 29582715 PMC: 5969546. DOI: 10.1080/15384101.2018.1445906.

Mitochondrial Transfer from Wharton's Jelly Mesenchymal Stem Cell to MERRF Cybrid Reduces Oxidative Stress and Improves Mitochondrial Bioenergetics.

Chuang Y, Liou C, Chen S, Wang P, Chuang J, Tiao M Oxid Med Cell Longev. 2017; 2017:5691215.

PMID: 28607632 PMC: 5457778. DOI: 10.1155/2017/5691215.

References

Fukuhara N, Tokiguchi S, Shirakawa K, Tsubaki T . Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities ): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J Neurol Sci. 1980; 47(1):117-33. DOI: 10.1016/0022-510x(80)90031-3. View

Shoffner J, Lott M, Lezza A, Seibel P, Ballinger S, Wallace D . Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990; 61(6):931-7. DOI: 10.1016/0092-8674(90)90059-n. View

Ching E, Attardi G . High-resolution electrophoretic fractionation and partial characterization of the mitochondrial translation products from HeLa cells. Biochemistry. 1982; 21(13):3188-95. DOI: 10.1021/bi00256a024. View

Anderson S, Bankier A, Barrell B, de Bruijn M, Coulson A, Drouin J . Sequence and organization of the human mitochondrial genome. Nature. 1981; 290(5806):457-65. DOI: 10.1038/290457a0. View

Chamberlain J . Fluorographic detection of radioactivity in polyacrylamide gels with the water-soluble fluor, sodium salicylate. Anal Biochem. 1979; 98(1):132-5. DOI: 10.1016/0003-2697(79)90716-4. View

KADENBACH B, Jarausch J, Hartmann R, Merle P . Separation of mammalian cytochrome c oxidase into 13 polypeptides by a sodium dodecyl sulfate-gel electrophoretic procedure. Anal Biochem. 1983; 129(2):517-21. DOI: 10.1016/0003-2697(83)90586-9. View

Byrne E, Trounce I, Marzuki S, Dennett X, Berkovic S, Davis S . Functional respiratory chain studies in mitochondrial cytopathies. Support for mitochondrial DNA heteroplasmy in myoclonus epilepsy and ragged red fibers (MERRF) syndrome. Acta Neuropathol. 1991; 81(3):318-23. DOI: 10.1007/BF00305874. View

Wallace D, Zheng X, Lott M, Shoffner J, Hodge J, Kelley R . Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell. 1988; 55(4):601-10. DOI: 10.1016/0092-8674(88)90218-8. View

Saiki R, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn G . Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988; 239(4839):487-91. DOI: 10.1126/science.2448875. View

10.

Singh G, Lott M, Wallace D . A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy. N Engl J Med. 1989; 320(20):1300-5. DOI: 10.1056/NEJM198905183202002. View

11.

Byrne E, Dennett X, Trounce I, Burdon J . Mitochondrial myoneuropathy with respiratory failure and myoclonic epilepsy. A case report with biochemical studies. J Neurol Sci. 1985; 71(2-3):273-81. DOI: 10.1016/0022-510x(85)90065-6. View

12.

Petty R, Harding A, Morgan-Hughes J . The clinical features of mitochondrial myopathy. Brain. 1986; 109 ( Pt 5):915-38. DOI: 10.1093/brain/109.5.915. View

13.

DiMauro S, Bonilla E, Zeviani M, Servidei S, DeVivo D, Schon E . Mitochondrial myopathies. J Inherit Metab Dis. 1987; 10 Suppl 1:113-28. DOI: 10.1007/BF01812852. View

14.

Byrne E, Trounce I . Oxygen electrode studies with human skeletal muscle mitochondria in vitro. A re-appraisal. J Neurol Sci. 1985; 69(3):319-33. DOI: 10.1016/0022-510x(85)90143-1. View

15.

Bresolin N, Zeviani M, Bonilla E, Miller R, Leech R, Shanske S . Fatal infantile cytochrome c oxidase deficiency: decrease of immunologically detectable enzyme in muscle. Neurology. 1985; 35(6):802-12. DOI: 10.1212/wnl.35.6.802. View

16.

Byrne E, Marzuki S, Dennett X . Current perspectives in the study of human mitochondriopathies. Med J Aust. 1988; 149(1):30-3. DOI: 10.5694/j.1326-5377.1988.tb120480.x. View

17.

Marzuki S, Sattayasai N, Trounce I, Byrne E . Protein synthesis in mitochondria isolated from human skeletal muscle. Detection of polymorphism in mitochondrial translation products. J Neurol Sci. 1988; 87(2-3):211-9. DOI: 10.1016/0022-510x(88)90246-8. View