Distribution and threshold expression of the tRNA[sup Lys] mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)
- Montreal Neurological Inst., Quebec (Canada)
- Montreal Neurological Inst., Quebec (Canada) McGill Univ., Montreal, Quebec (Canada)
The authors investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA[sup Lys] gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA[sup Lys] is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype. 40 refs., 7 figs., 2 tabs.
- OSTI ID:
- 6717632
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 51:6; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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Segregation and manifestations of the mtDNA tRNA[sup Lys] A[r arrow]G[sup (8344)] mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome
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Related Subjects
CYTOCHROME OXIDASE
ENZYME ACTIVITY
MITOCHONDRIA
METABOLIC DISEASES
TRANSFER RNA
RECESSIVE MUTATIONS
DISTRIBUTION
EPILEPSY
FIBERS
GENES
LEVELS
LYSINE
MUSCLES
MYOBLASTS
PATIENTS
PHENOTYPE
RESIDUES
SIZE
AMINO ACIDS
CARBOXYLIC ACIDS
CELL CONSTITUENTS
DISEASES
ENZYMES
HAEM DEHYDROGENASES
MUTATIONS
NERVOUS SYSTEM DISEASES
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
OXIDOREDUCTASES
PROTEINS
RNA
550400* - Genetics