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3.6Gain-of-Function Mutations

Fig. 3-4 Gain-of-function and Phenotypes

Fig. 3-5 Haploinsufficiency

Many mutations are of the loss-of-function type, and in such cases, the mutated trait is commonly inherited recessively. However, the mutated trait is inherited as a dominant trait in some comparatively rare cases. This is observed when the mutation results in a protein having another abnormal function (gain-of-function mutation). The gained function may be inherited as a dominant trait (Fig. 3-4). Loss-of-function mutations may also be inherited as dominant traits. Proteins with intracellular activity are hypothesized to cause disease when they exist at less than 70% of their normal amount. In F1 offspring with the Aa genotype, who are born from parents with AA and aa genotypes, a disease occurs when the wild-type and loss-of-function-type proteins are produced at a ratio of 1:1 because the amount of the wild-type protein produced is insufficient, being only 50%. In other words, the a genotype for the loss-of-function mutation appears to have been inherited as a dominant trait. This is called haploinsufficiency (Chapter 24, Fig. 3-5). In such cases, if the amount of the wild-type protein does not change even when the a gene with mutation is introduced into an AA cell and overexpressed, then no disease occurs. However, if the a gene with loss-of-function mutation is introduced from outside into the AA cell and overexpressed, an abnormality may occur. If the protein functions as a complex, such as a dimer or tetramer, then a mutant trait occurs because complexes of normal proteins are only found in extremely small amounts. A mutant is often dominant in Aa heterozygotes, if the protein functions as a dimer because the normal protein comprises approximately 25% of the complex. If the protein functions as a tetramer, then the percentage might be even less. Thus, the event of a loss-of-function trait being dominant is called “dominant negative.” In humans, Alzheimer’s and Huntington’s diseases occur because of genetic mutations, and the mutated trait in these diseases is dominant.

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