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ABSTRACT: Large-scale heteroplasmic mtDNA rearrangements were identified in a 57-year-old woman with chronic depressive disorder, hearing-loss, diabetes mellitus and a slowly progressive encephalomyopathy. A high percentage of a 24.2 kb duplicated molecule was found in lymphocytes whereas the corresponding deletion dimer dominated in muscle. PCR and Southern blot analyses were used to identify a 7658 bp duplication/deletion fragment. The duplicated mtDNA disrupted the cytochrome oxidase subunit I and cytochrome b genes at a position where there were no direct repeats. Duplicated mtDNA was not observed in the mother and brother of the patient. Histochemical analysis of skeletal muscle demonstrated pathological accumulation of mitochondria in cytochrome c oxidase negative fibers. In situ hybridization demonstrated only deleted mtDNA in cytochrome c oxidase negative fibres. We conclude that occurrence of deleted mtDNA correlates with phenotypic expression and that the duplicated mtDNA might serve as a generator of deletions, but is not directly pathogenic.
Neuromuscular Disorders 04/2004; 14(3):195-201. · 2.80 Impact Factor
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ABSTRACT: During intracytoplasmic sperm injection (ICSI) the whole sperm, including head, midpiece and tail, is injected into the middle
area of the oocyte. To find out what happens to the sperm mitochondria after ICSI, we checked the first six children born
after ICSI treatment for occurrence of paternal mitochondrial DNA (mtDNA). The difference between maternal and paternal mtDNA
in the investigated couples in our study was confined to single-base pair substitutions and we had to rely on restriction
enzyme cleavage to differentiate between the mitochondrial genomes of the parents. With this kind of assay we were able to
reach a sensitivity of about 0.2% for the paternal mtDNA. However, as uneven partition between tissues of heteroplasmic mtDNA
is expected to occur, it would not be unlikely that an enrichment to 0.2% would occur in a given tissue if paternal mtDNA
was transmitted by the ICSI procedure. We did not detect this level in the blood in any of the six children.
Journal of Assisted Reproduction and Genetics 04/1997; 14(4):223-227. · 1.84 Impact Factor
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ABSTRACT: A girl, who died at 14 years of age from a rapidly progressive mitochondrial myopathy, was found to be heteroplasmic for a mutation in the mitochondrial tRNALeu(UUR) gene at position 3251. A large proportion of muscle fibres contained accumulations of abnormal mitochondria but no cytochrome c oxidase deficient fibres were present. Polarographic and enzymatic measurements on isolated muscle mitochondria revealed a profound isolated complex I deficiency. A high percentage of mutant mtDNA was found in muscle (94%), fibroblasts (93%), brain (90%), liver (80%), and heart (79%). The family was not available for investigation. For genotype to phenotype correlation studies, we investigated the proportion of mutated mtDNA in single muscle fibres of normal appearance and muscle fibres with accumulations of mitochondria. The proportion of mutant mtDNA was 28% (range < 0.3%–86%) in normal-appearing fibres and 61% (range 15%–88%) in abnormal fibres. The difference in the proportion of mutant mtDNA was highly significant (P < 0.001) between the two groups of fibres.
Human Genetics 02/1996; 97(3):269-273. · 5.07 Impact Factor
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ABSTRACT: The mutation in the mitochondrial ATP synthase subunit 6 gene (ATP6 T8993G) was identified in a male infant who died at age 15 months of Leigh syndrome. He had 94% mutated mitochondrial DNA (mtDNA) in muscle and 92% in lymphocytes. His mother was healthy but had 37% mutated mtDNA in muscle and 38% in lymphocytes. The proband's brother, who was also healthy, had 44% mutated mtDNA in lymphocytes. No mutated mtDNA was detected in muscle and lymphocytes from the maternal grandmother of the proband or in lymphocytes from 15 other maternal relatives, showing that the first carrier of the ATP6 T8993G mutation in this family was the mother of the proband. This study shows that this point mutation may occur at substantial levels in a carrier of a de novo mutation and rapid segregation with high levels of mutated mtDNA causing neurodegenerative disease may occur in the second generation.
Human Genetics 08/1995; 96(3):290-294. · 5.07 Impact Factor
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ABSTRACT: We have investigated nine children with infantile onset of mitochondrial myopathy and two adults with myoclonus epilepsy and ragged-red fibers (MERRF) and chronic progressive external ophthalmoplegia (CPEO), respectively. These patients lacked any of the previously known pathogenic tRNA mutations. Southern blot analysis of muscle mtDNA revealed no deletions. The tRNA genes of muscle mtDNA were sequenced. Restriction enxyme analysis of PCR fragments was performed to verify the presence of the mutations identified by automatic sequencing. Several tRNA mutations were found, but they were all homoplasmic. Furthermore, the mutations were either present in controls or did not change nucleotides conserved between species. This strongly suggests that none of the tRNA mutations identified in the 11 patients with mitochondrial encephalomyopathy was pathogenic. It can thus be concluded that mitochondrial tRNA mutations and mtDNA deletions probably are an infrequent cause of mitochondrial disorders in infants. Patients with MERRF and CPEO may lack both pathogenic point mutations of tRNA genes and deletions of mtDNA.
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
