Dosage Sensitivity - Example

Pedigree

If the phenotypic expression of a genotype depends upon whether one or two alleles of the abnormal gene are present, then dosage sensitivity is present. In the above pedigree representative abnormal total serum cholesterol values are given (in mg/dL).

Familial Hypercholesterolemia

This is an example of a mutation which leads to dosage sensitivity. The gene codes for a protein that forms the LDL cholesterol receptor in arteries. Persons with the normal allele have normal numbers of LDL receptors and normal cholesterol levels <200 mg/dL. Persons heterozygous with an abnormal gene have 50% fewer LDL receptors and cholesterol levels around 300 to 400 mg/dL. Homozygotes have virtually no LDL receptors and cholesterol levels can exceed 600 mg/dL. Since the carrier rate is 1 in 500 in the U.S., the disease is not rare, but the homozygous condition is seen in 1 per million.