caa a22 4500 397575440 CHVBK 20180308164854.0 cr unu---uuuuu 161202e199611 xx s 000 0 eng 10.1093/hmg/5.11.1835 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.11.1835 A Novel Heteroplasmic tRNAleu(CUN) mtDNA Point Mutation in a Sporadic Patient With Mitochondrial Encephalomyopathy Segregates Rapidly in Skeletal Muscle and Suggests an Approach to Therapy [Elektronische Daten] [Katherine Fu, Rebecca Hartlen, Timothy Johns, Angela Genge, George Karpati, Eric A. Shoubridge] A novel mtDNA point mutation was detected in the tRNAleu(CUN) gene (G to A at position 12315) in a sporadic patient with chronic progressive external ophthalmoplegia, ptosis, limb weakness, sensorineural hearing loss and a pigmentary retinopathy. The mutation disrupts base pairing in the TΨC stem at a site which has been conserved throughout evolution. Although the other mtDNA tRNAleu gene (UUR) is a hotspot for mutation, this is the first pathogenic mutation to be reported in the gene coding for tRNAleu(CUN). MtDNAs carrying the mutation constituted 94% of total mtDNAs in two separate muscle biopsies. Single fibre analysis showed that skeletal muscle fibres without detectable cytochrome c oxidase activity (COX-ve fibres) contained predominantly mutant mtDNAs (93-98%) while fibres with apparently normal COX activity had up to 90% mutant mtDNAs, demonstrating that the G12315A mutation is functionally recessive. Immunofluorescence studies with specific antibodies to mtDNA- or nuclear-encoded subunits of COX were consistent with a defect in mitochondrial protein translation. The mutation was not present in blood cells or cultured fibroblasts and surprisingly, it could not be detected in satellite cells cultured from the patient's muscle. This pattern, which may be typical of patients who have inherited new germline pathogenic mtDNA mutations, possibly reflects loss of the mutation by random genetic drift in mitotic tissues and proliferation of mitochondria containing the mutant mtDNA in post-mitotic cells. The absence of mtDNA carrying the mutation in satellite cells suggests that regeneration of skeletal muscle fibres from satellite cells could restore a wild-type mtDNA genotype and normal muscle function. © 1996 Oxford University Press Fu Katherine Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Hartlen Rebecca Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Johns Timothy Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Genge Angela Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Karpati George Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Shoubridge Eric A. Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut Human Molecular Genetics Oxford University Press 5/11(1996-11), 1835-1840 0964-6906 5:11<1835 1996 5 hmg https://doi.org/10.1093/hmg/5.11.1835 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.11.1835 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Fu Katherine Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 700 1- Hartlen Rebecca Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 700 1- Johns Timothy Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 700 1- Genge Angela Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 700 1- Karpati George Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 700 1- Shoubridge Eric A. Montreal Neurological Institute, 3801 University Street, Montreal Quebec, Canada and H3A 2B4 aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/11(1996-11), 1835-1840 0964-6906 5:11<1835 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford