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autosomal dominant diseases

Thursday 2 March 2006

Definition: Only one mutated copy of the gene is needed for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent. There is a 50% chance that a child will inherit the mutated gene.

Autosomal dominant disorders are manifested in the heterozygous state, so at least one parent of an index case is usually affected; both males and females are affected, and both can transmit the condition.

When an affected person marries an unaffected one, every child has one chance in two of having the disease. In addition to these basic rules, autosomal dominant conditions are characterized by the following

With every autosomal dominant disorder, some patients do not have affected parents. Such patients owe their disorder to new mutations involving either the egg or the sperm from which they were derived. Their siblings are neither affected nor at increased risk for developing the disease.

The proportion of patients who develop the disease as a result of a new mutation is related to the effect of the disease on reproductive capability.

If a disease markedly reduces reproductive fitness, most cases would be expected to result from new mutations. Many new mutations seem to occur in germ cells of relatively older fathers

Clinical features can be modified by reduced penetrance and variable expressivity. Some individuals inherit the mutant gene but are phenotypically normal. This is referred to as reduced penetrance.

Penetrance is expressed in mathematical terms: Thus, 50% penetrance indicates that 50% of those who carry the gene express the trait. In contrast to penetrance, if a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals, the phenomenon is called variable expressivity.

For example, manifestations of neurofibromatosis type 1 range from brownish spots on the skin to multiple skin tumors and skeletal deformities.

The mechanisms underlying reduced penetrance and variable expressivity are not fully understood, but they most likely result from effects of other genes or environmental factors that modify the phenotypic expression of the mutant allele.

For example, the phenotype of a patient with sickle cell anemia (resulting from mutation at the β-globin locus) is influenced by the genotype at the α-globin locus because the latter influences the total amount of hemoglobin made.

The influence of environmental factors is exemplified by familial hypercholesterolemia. The expression of the disease in the form of atherosclerosis is conditioned by the dietary intake of lipids

In many conditions, the age at onset is delayed: symptoms and signs do not appear until adulthood (as in Huntington disease

The biochemical mechanisms of autosomal dominant disorders are best considered in the context of the nature of the mutation and the type of protein affected. Most mutations lead to the reduced production of a gene product or give rise to an inactive protein.

The effect of such loss of function mutations depends on the nature of the protein affected. If the mutation affects an enzyme protein, the heterozygotes are usually normal. Because up to 50% loss of enzyme activity can be compensated for, mutation in genes that encode enzyme proteins do not manifest an autosomal dominant pattern of inheritance.

By contrast, two major categories of nonenzyme proteins are affected in autosomal dominant disorders

- 1. Those involved in regulation of complex metabolic pathways that are subject to feedback inhibition: Membrane receptors such as the LDL receptor provide one such example; in familial hypercholesterolemia, discussed in detail later, a 50% loss of LDL receptors results in a secondary elevation of cholesterol that, in turn, predisposes to atherosclerosis in affected heterozygotes.

- 2. Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane (e.g., spectrin): The biochemical mechanisms by which a 50% reduction in the levels of such proteins results in an abnormal phenotype are not fully understood.

In some cases, especially when the gene encodes one subunit of a multimeric protein, the product of the mutant allele can interfere with the assembly of a functionally normal multimer.

For example, the collagen molecule is a trimer in which the three collagen chains are arranged in a helical configuration.

Each of the three collagen chains in the helix must be normal for the assembly and stability of the collagen molecule. Even with a single mutant collagen chain, normal collagen trimers cannot be formed, and hence there is a marked deficiency of collagen.

In this instance, the mutant allele is called dominant negative because it impairs the function of a normal allele. This effect is illustrated by some forms of osteogenesis imperfecta, characterized by marked deficiency of collagen and severe skeletal abnormalities

Less common than loss of function mutations are gain of function mutations.

As the name indicates, in this type of mutation, the protein product of the mutant allele acquires properties not normally associated with the wild-type protein. The transmission of disorders produced by gain of function mutations is almost always autosomal dominant, as illustrated by Huntington disease.

In this disease, the trinucleotide repeat mutation affecting the Huntington gene (see later) gives rise to an abnormal protein. The mutant huntingtin protein is toxic to neurons, and hence even heterozygotes develop neurologic deficit

To summarize, two types of mutations and two categories of proteins are involved in the pathogenesis of autosomal dominant diseases.

The more common loss of function mutations affect regulatory proteins and subunits of mulitmeric proteins, the latter acting through a dominant negative effect.

Gain of function mutations are less common; they endow normal proteins with toxic properties and hence affect the function of other proteins encoded by the mutant gene.

Some examples

- Huntingtons disease
- neurofibromatosis type 1
- hereditary nonpolyposis colorectal cancer (HNPCC)

See also

- genetic diseases

  • monogenic diseases