SupplementMitochondrial DNA and disease
Section snippets
Basic mitochondrial genetics
Each mtDNA molecule contains 13 polypeptide-encoding genes, and the 24 RNA genes that allow intramitochondrial protein synthesis (figure). Transcription and translation of mtDNA is controlled by the nucleus through the only non-coding region of the mitochondrial genome (the 1 kb D-loop). The polypeptides synthesised from the 13 mtDNA genes interact with more than 60 nuclear-encoded polypeptides to form the mitochondrial respiratory chain, which is essential for aerobic cellular metabolism.
Differences between nuclear and mtDNA
There are two fundamental differences between nuclear DNA and mtDNA that are important for the expression and transmission of mitochondrial genetic disease.
Clinical range and prevalence of mtDNA disease
A number of well-defined clinical syndromes are caused by mutations of mtDNA (panel 2).7 Large-scale deletions can cause chronic progressive external ophthalmoplegia (CPEO) and bilateral ptosis19 Some of these patients have little disability and may have limited extramuscular involvement. By contrast, similar deletions may also cause CPEO with bilateral sensorineural deafness, cerebellar ataxia, pigmentary retinopathy, diabetes mellitus, and cardiac conduction defects leading to complete heart
Genetic tests for mtDNA disease
Not all patients with mtDNA disease can be diagnosed by a simple molecular genetic blood test that looks for one of the more common mtDNA mutations: a negative blood test in an index case does not mean that an individual does not have mtDNA disease. There are many potential difficulties. The same clinical phenotype can be caused by many different mutations, and even if the phenotype is “classic” for a particular genetic defect, the proportion of mutated mtDNA in blood may be undetectable by the
Conclusion
Defects of the mitochondrial genome are a common cause of genetic disease. Many patients have sporadic disease due to deletions, but maternally inherited point mutations are common. Patients with pathogenetic mtDNA defects often have a mixture of mutated and wild-type mtDNA—heteroplasmy—which is “important for the expression and transmission of mtDNA disease. The investigation of patients with suspected mtDNA disease is a challenge, partly because of the complexities of the mitochondrial
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