Human Molecular Genetics, Vol 5, 1835-1840, Copyright © 1996 by Oxford University Press
K Fu, R Hartlen, T Johns, A Genge, G Karpati and EA 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 T psi C
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 by 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.
ARTICLES
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
Montreal Neurological Institute, Quebec, Canada.
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