Comparatively few human disorders have been shown to be mitochondrially inherited, and most of these are rare. To date only one mitochondrial (maternally inherited) pharmacogenetic trait has been identified (see Appendix A). The occurrence of this disorder depends on exposure to aminoglycoside antibiotics and its prevalence has not been established.
Mitochondrial DNA (mtDNA) is predominantly inherited from the mother (see p. 1 03). Male germ cells (spermatozoa) contain very little cytoplasm and are estimated to contribute less than 0. 1 % of the zygote's mtDNAs. Cells can harbor mixtures of mutant and normal mtDNA (heteroplasmy). Each time a somatic or germ cell line divides, the mutant and normal mtDNAs segregate randomly into daughter cells. The mtDNA genotypes may fluctuate from one cell division to the next, and over many cell divisions the proportion of mutant mtDNAs drifts toward predominantly mutant or normal mtDNA (homoplasmy). The severity of the defect results from the nature of the mtDNA mutation, and the proportion of mutant mtDNAs within the cell; the clinical picture in maternal relatives of heteroplasmic pedigrees varies according to the proportion of mutant mtDNAs that each individual inherits.
While mitochondria are predominantly inherited only from the mother, and some mitochondrial disorders are maternally inherited, recent studies indicate that the great majority—more than 80%—of diseases known to be linked to faulty mitochondria are due to nuclear genes and do not exhibit maternal inheritance. Evidence that mitochondrial proteins are responsible for human disease is growing, but currently, the actual contribution of nuclear genes to mitochondrial disease is unclear because we do not yet know which genes are involved and how they interact with mitochondrial genes.30
The possibility of sex (X)-linked inheritance should be considered when maternal transmission is encountered, but can be excluded if both sexes are equally affected, or if males do not transmit the susceptibility to their daughters or to their grandsons through an affected daughter (Figure 5.5).31
Certain traits of pharmacogenetic interest do not always follow one of the orthodox patterns of inheritance and may be less straightforward to analyze. For example, responses to exogenous chemicals that involve a combination of monogenic traits usually do not yield such a simple inheritance pattern. Other responses that have been discovered recently and have unorthodox inheritance patterns include traits that are determined by trinucleotide repeats, ''jumping genes'' or other types of unstable genes, or genes that assume alternate forms and may produce more than one protein.
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