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8.1. Gene Therapy of Mitochondrial Diseases
Yasuo Kagawa.
Jichi Medical School, Japan
There are large ethnic differences in the frequency of genetic diseases. Cystic fibrosis, the most common target of genetic treatment in Caucasians, sickle cell anemia, very common in Negroids, and thalassemia, common in the Mediterranean population, are described in many foreign textbooks. However, these are not found among Japanese. The most frequent genetic disease caused by a single gene in Japanese is mitochondrial. The disease of about 1-3% of the 6 million diabetics is caused by mitochondrial mutation, and over 100,000 involve the MELAS mutation discussed below (1). This can result in diabetic nephropathy and many other conditions. Mitochondria (mt) are the sites of oxidative phosphorylation,and thus, the highly energy-dependent brain and muscle are often affected by mt mutation (2). This is mt encephalomyopathy, which is often accompanied by lactic acidosis as a result of a compensatory increase in glycolysis. In the muscle pathological mt known as "Ragged red fiber" is found to increase, and crystalline inclusions are found in electron micrographs of mt.
There are point mutations (Leber's disease etc.),and deletions (KSS:Kearns-Sayre syndrome etc.) in mtDNA, as in nuclear DNA, but diseases of protein synthesis caused by defective mt-tRNA arising from point or deletion mutations are most frequent. The three major clinical types of mt-encephalomyopathies are KSS, MELAS and MERRF. MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes) is a mutation of tRNA (Leu,UUR)and a #3243 (A to G) mutation is the most frequent. The symptoms are poplexia, hemiplegia, partial blindness,neural deafness etc. MERRF (myoclonus epilepsy with ragged red fibers) is caused by a mutation of tRNA(Lys) at #8,344 (A to G), and is characterized by myoclonus epilepsy. KSS is caused by a partial deletion of mtDNA, and the onset of trias (external ophthalmoplegia, atypical retinosis pigmentosa, and disturbance in cardiac conductance) before 15 years old. When all the mtDNA in a cell is affected, this is known as homoplasmy. However, in most clinical cases, both normal and mutated mtDNA are mixed in a cell (heteroplasmy). Mt genes are maternally inherited, and the severity of symptoms depends on the degree of heteroplasmy. Since most mt proteins are encoded by nuclear DNA, there are also many mt diseases caused by nuclear genes.
In order to analyze mt diseases, cells devoid of mtDNA, called o (rho zero), and cells with no nucleus called cytoplasts are fused together, and in this way, diseases caused by mtDNA and nuclear DNA can be differentiated. The analysis of mutant DNA promoted fetal diagnosis and gene therapy. A new type of gene therapy using cytoplasts is also being developed (4). Since mtDNA is expressed equally in all tissues, tissue-specificity of muscle mt etc.is determined by alternate splicing (5). A control system for the transcription and splicing due to the signal transduction is needed for the future elucidation of mt disease.
Since the mutation rate of mtDNA is about 10 times that of nuclear DNA, genetic diseases caused by mtDNA mutation are on the increase, and are rapidly accumulating in modern society where practically no natural selection exists. However, in Japan, abortion because of genetic diseases discovered by fetal diagnosis is officially forbidden by the Gynecological Society. However the parents cannot take care of the child to be born to the end of the later's life. If this irresponsible attitude of the Gynecological Society continues, genetic diseases will accumulate in a society with no natural selection, and at some point in the future the consensus against abortion will breakdown. In Japan, the cost of fetal diagnosis is not paid for by public insurance. This has th paradoxical result of increasing the burden on society and leading to the present state where we face a shortage of resources. Unfortunately, many Japanese scholars of bioethics insist on a "social consensus" consistent with their own views and "fetal rights". Thus, the prevention of genetic disease by prenatal diagnosis called for by public opinion is not discussed openly. As a result, patients and their families cannot receive proper consultation, and their health and life may be threatened.
Finally, while human cloning is promising as a solution to regeneration and aging, its ELSI (ethical, legal, social issue) need to be discussed. The present cloning technology depends on an oocyte, and a human clone would not be the exact copy of their somatic cell, rather oocyte mt is involved.
References
1. Kagawa Y:Japan. J Internal Med 84: 135 (1995)
2. Wallace DC:Ann Rev Biochem 61: 1175 (1992)
3. Hayashi J-I, Ohta S, Kagawa Y et al.:J Biol Chem 269: 19060 (1994)
4. Kagawa, Y. and Hayashi, J-I.: Gene Therapy 4: 6 (1997)
5. Endo,H., Matsuda,C. and Kagawa, Y.: J Biol Chem 269: 12488 (1994)
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