Autosomal Dominant Inheritance - Examples

Pedigree

The disease is represented in each generation. Male and female offspring are equally likely to inherit the trait. Half of offspring are affected, on average.

Osteogenesis Imperfecta

An example of a mutation involving a gene encoding for a structural protein is osteogenesis imperfecta (OI). Structural genes tend to be quite large (many kilobases) and so mutations can occur at a variety of places, so a variety of mutations can involve the same gene, and this explains variations in the expression of the mutation. Thus, because the OI gene is large (over 50 exons) mutations can occur in a variety of places, and the result is different expressions of the disease. Since big genes are more prone to mutation, this also explains why mutations involving structural genes are more likely to arise de novo than be inherited. OI is a disorder based upon abnormal collagen formation, leading to abnormal bone matrix production and abnormal bone tha fractures easily. Collagen is a large, complex molecule that requires multiple steps for production. OI mutations are in a gene encoding for type I collagen. Since even in heterozygotes abnormal protein is made and incorporated into collagenous structures, there is expression of the abnormality. Thus, mutations in structural genes tend to be expressed in a dominant fashion. OI is an example of a "dominant negative" mutation in which the loss of function disturbs the product of other normal genes encoding for the multimeric protein.

Marfan Syndrome

Marfan syndrome is another example of an autosomal dominant condition involving a structural gene, in this case the fibrillin gene, which encodes for a protein that is a component of microfibrils that form connective tissues, particularly in the aorta, eye, and skeletal system. Affected persons are tall, with long fingers (arachnodactyly), loose joints, ocular problems, and a propensity for the aorta to rupture. Thus, the fibrillin gene leads to pleiotropism. Structural genetic diseases are often good examples of a "gain of function" mutation because heterozygotes and homozygotes express the disease similarly. The gene product is overexpressed or inappropriately expressed in development. The result is the appearance of a dominant trait.