Mitochondrial DNA Mutations as an Etiology of Human Degenerative Diseases
Because mitochondrial DNA (mtDNA) is exclusively maternally transmitted, mutations of mtDNA are implicated to be the cause of maternally inherited diseases. Recent extensive studies have clarified three types of mtDNA mutations in several human diseases.
Type A, homoplasmy: A base transition from guanine at nucleotide number 11,778 to adenine converts the 340th arginine to histidine in the ND4 subünit of Complex I. This maternally inherited mutation was found both in American pedigrees and in Japanese pedigrees of Leber's hereditary optic neuropathy.
Type B, heteroplasmy: Heteroplastic existence of mutant mtDNA with a multi-gene deletion with the normal-sized mtDNA was found in 1/3 of patients with Kearns-Sayre syndrome (KSS) and chronic progressive external ophthalmoplegia (CPEO). The population of the deleted mtDNA was large enough to be detected by the conventional Southern blot analysis. This group of patients showed early onset of clinical symptoms and no family history. The location of the deletion in each individual was precisely determined by the combination of polymerase chain reaction and S1 nuclease digestion (PCR plus S\ method). Direct sequencing of the boundaries of the deletions revealed that the deletions occur between 3~13-bp directly repeated sequences.
Type C, pleioplasmy: Pleioplasmic existence of mutated mtDNAs with various deletions with the normal-size mtDNA was found in 2/3 of patients with mitochondrial myopathy. The population of each mutated mtDNA was so small that the existence could not be detected by the Southern blot analysis but by the PCR amplification. The deletions were confirmed by comparing the shift in the positions of the primers used for amplification with the shift in the sizes of the amplified DNA fragments (primer-shift PCR method). PCR direct sequencing of the one of the deletions in patients with pleioplasmic deletions showed a 13-bp directly repeated sequence which was identical with the sequence found in patients with homoplasmic deletion. The patients with pleioplasmic deletions showed late onset of clinical symptoms. About a half of the patients had a positive family history.
Pleioplasmic mtDNA deletions were also found in patients with exertional myoglobinuria without external ophthalmoplegia and in patients with cardiomyopathy. It is proposed that accumulation of mtDNA mutations and subsequent cytoplasmic segregation of these mutations during life is an important contributor both to the ageing process and to several human degenerative diseases. Since pleioplasmic mtDNA deletions can be analyzed semiquantitatively by using PCR, this type of mutation would be a useful indicator of the levels of accumulation of mtDNA mutations in age-related degenerative disorders.
KeywordsSouthern Blot Analysis Mitochondrial Myopathy Chronic Progressive External Ophthalmoplegia Multiple Deletion Chronic Progressive External Ophthalmoplegia
Unable to display preview. Download preview PDF.
- 18.Rowland, L.P. (1984) In: Rowland LP ed. Merritt's textbook of neurology. 7th ed. Philadelphia, Lea and Febiger, 585–590.Google Scholar
- 19.Sato, W., Tanaka, M., Sugiyama, S., Hattori, K., Ito, T., Kawaguchi, H., Onozuka, H., Yasuda, H., Ito, K., Tashiro, K., Ohno, K., Yamamoto, T., Takada, G., and Ozawa, T. (submitted)Google Scholar