Abstract
Mitochondrial respiratory chain defects are associated with diverse clinical phenotypes
in both adults and children, and may be caused by mutations in either nuclear or mitochondrial
DNA (mtDNA). We report the molecular genetic investigations of a patient with chronic
progressive external ophthalmoplegia (CPEO) and myopathy where muscle biopsies taken
11 years apart revealed a progressive increase in the proportion of cytochrome c oxidase (COX)-deficient fibres. Mitochondrial genetic analysis of the early biopsy
had seemingly excluded both mtDNA rearrangements and mtDNA point mutations. Sequencing
mtDNA from individual COX-deficient muscle fibres in the second biopsy, however, identified
an unreported m.14723 T>C substitution within the mitochondrial tRNAGlu (MTTE) gene, which fulfilled all canonical criteria for pathogenicity. The m.14723 T>C mutation was absent from several tissues, including muscle, from maternal relatives
suggesting a de novo event, whilst quantitative analysis of the first muscle biopsy confirmed a very low
level of the mutation (7% mutated mtDNA), highlighting a potential problem whereby
pathogenic mtDNA mutations may remain undetected using established screening methodologies.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- A functionally dominant mitochondrial DNA mutation.Hum Mol Genet. 2008; 17: 1814-1820
- Mitochondrial DNA mutations in human disease.Am J Med Genet. 2001; 106: 18-26
- Prediction of pathogenic mutations in mitochondrially encoded human tRNAs.Hum Mol Genet. 2005; 14: 2415-2419
- Assigning pathogenicity to mitochondrial tRNA mutations: when “definitely maybe” is not good enough.Trends Genet. 2004; 20: 591-596
- Noninvasive diagnosis of the 3243A > G mitochondrial DNA mutation using urinary epithelial cells.Eur J Hum Genet. 2004; 12: 778-781
- Methods of microphotometric assay of succinate dehydrogenase and cytochrome c oxidase activities for use on human skeletal muscle.Histochem J. 1989; 21: 545-555
- Mitochondrial DNA deletion in “identical” twin brothers.J Med Genet. 2004; 41: e19
- The determination of complete human mitochondrial DNA sequences in single cells: implications for the study of somatic mitochondrial DNA point mutations.Nucleic Acids Res. 2001; 29: E74
- Mitochondrial DNA mutations in human colonic crypt stem cells.J Clin Invest. 2003; 112: 1351-1360
- Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet. 1999; 23: 147
- Accurate detection and quantitation of heteroplasmic mitochondrial point mutations by pyrosequencing.Genet Test. 2005; 9: 190-199
- A standard reference material to determine the sensitivity of techniques for detecting low-frequency mutations, SNPs, and heteroplasmies in mitochondrial DNA.Genomics. 2005; 86: 446-461
- A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.Am J Hum Genet. 1997; 60: 373-380
- An enhanced MITOMAP with a global mtDNA mutational phylogeny.Nucleic Acids Res. 2007; 35: D823-D828
- mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences.Nucleic Acids Res. 2006; 34: D749-D751
- A novel sporadic mutation G14739A of the mitochondrial tRNAGlu in a girl with exercise intolerance.Neuromusc Disord. 2006; 16: 874-877
- Mitochondrial myopathy and respiratory failure associated with a new mutation in the mitochondrial transfer ribonucleic acid glutamic acid gene.J Child Neurol. 2003; 18: 300-303
- Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes.Mol Genet Metab. 2005; 84: 176-188
- Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus.Am J Hum Genet. 1995; 56: 1017-1025
- Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation.Am J Hum Genet. 1995; 56: 1026-1033
- Molecular epidemiology of childhood mitochondrial encephalomyopathies in a Finnish population: sequence analysis of entire mtDNA of 17 children reveals heteroplasmic mutations in tRNAArg, tRNAGlu, and tRNALeu(UUR) genes.Pediatrics. 2004; 114: 443-450
- Identification of a new mtDNA mutation (14724G > A) associated with mitochondrial leukoencephalopathy.Biochem Biophys Res Commun. 2007; 354: 937-941
- Mitochondrial encephalomyopathy due to a novel mutation in the tRNAGlu of mitochondrial DNA.J Child Neurol. 2007; 22: 858-862
- Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.Brain. 2009; 132: 3165-3174
- Pathogenic mitochondrial tRNA mutations — which mutations are inherited and why?.Hum Mutat. 2009; 30: E984-E992
- Neuromuscular disease presentation with three genetic defects involving two genomes.Neuromuscul Disord. 2009; 19: 841-844
Article info
Publication history
Published online: September 01, 2010
Accepted:
August 6,
2010
Received in revised form:
July 30,
2010
Received:
July 9,
2010
Identification
Copyright
© 2010 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
