Mitochondrial Gene Disorders
The mitochondria contain their own DNA, which is distinct from the DNA contained in the cell nucleus. There are multiple disease-affected rearrangements and point mutations. Mitochondrial DNA (mtDNA) is packaged in a double-stranded circular chromosome located inside the mitochondria. Mitochondrial DNA contains 37 genes: 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes, and 13 structural genes encoding subunits of the mitochondrial respiratory chain enzymes, which participate in oxidative phosphorylation and generation of adenosine triphosphate.
In contrast to the mendelian pattern of inheritance of nuclear DNA, disorders of mtDNA are inherited on the maternal line. This can be explained by the fact that ova contain numerous mitochondria in their abundant cytoplasm, whereas spermatozoa contain few, if any, mitochondria. Thus, the mtDNA in the zygote is derived solely from the mother. The zygote and its daughter cells have many mitochondria, each of which contains multiple copies of the maternally derived mtDNA. During growth of the fetus or later, it is likely that some cells will contain only normal or mutant mtDNA (a situation called homoplasmy), whereas others receive a mixture of normal and mutant DNA (heteroplasmy). In turn, the clinical expression of a disease produced by a given mutation of mtDNA depends on the total content of mitochondrial genes and the proportion that is mutant. The fraction of mutant mtDNA must exceed a critical value for a mitochondrial disease to become symptomatic. This threshold varies in different organs and is presumably related to the energy requirements of the cells.
Mitochondrial DNA mutations generally affect tissues that are dependent on oxidative phosphorylation to meet their high needs for metabolic energy. Thus, mtDNA mutations frequently affect the neuromuscular system and produce disorders such as encephalopathies, myopathies, retinal degeneration, loss of extraocular muscle function, and deafness. The range of mitochondrial diseases is broad, however, and may include liver dysfunction, bone marrow failure, and pancreatic islet cell dysfunction and diabetes, among other disorders. Table 7.2 describes representative examples of disorders due to mutations in mtDNA.