Nuclear gene causing multiple mtDNA deletions in autosomal dominant ophthalmoplegia maps to a distinct chromosomal region - involvement of both nuclear and mitochondrial DNA in a single disorder
- Univ. of Helsinki (Finland); and others
Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by muscle weakness, most prominent in ocular muscles. The symptoms are caused by accumulation of multiple large deletions of mitochondrial DNA (mtDNA) in the tissues of the patient, especially in those tissues that are most dependent on oxidative metabolism: brain, skeletal muscle and heart. However, the disorder shows autosomal dominant way of transmission, suggesting a primary defect in a nuclear encoded protein, which only secondarily results in mtDNA deletions. The candidate genes could be those actively participating in the mtDNA replication, or those associated with oxidative metabolism and e.g. via overproduction or inefficient elimination of fire oxygen radicals fragmenting mtDNA. We applied random mapping approach to localize the autosomal adPEO gene locus in a large Finnish family. The affected subjects were identified by detection of multiple mtDNA deletions in the Southern blot analysis of DNA extracted from the muscle biopsy specimens. All the family members underwent muscle biopsy. After analysis of 248 highly polymorphic dinucleotide repeat markets dispersed throughout the genome we were able to assign the adPEO gene locus to a distinct chromosomal region with the maximum pairwise lod score of 4.52, recombination fraction 0.0. This is the first evidence that a mutation in a nuclear gene may interfere mtDNA. The pathogenesis of adPEO involves both the genomes: the primary nuclear gene defect leads to secondary mtDNA mutations that cause the symptoms of the patients.
- OSTI ID:
- 133309
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0036
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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