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.

Top of Page