Loss-of-Function Mutations

The loss of function of a gene may result from alteration of its coding, regulatory, or other critical sequences due to nucleotide substitutions, deletions, insertions, or rearrangements. A loss of function due to deletion, leading to a reduction in gene dosage, is exemplified by the α-thalassemias (Case 44), which are most commonly due to deletion of α-globin genes (see later discussion); by chromosome-loss diseases (Case 27), such as monosomies like Turner syndrome (see Chapter 6) (Case 47); and by acquired somatic mutations—often deletions—that occur in tumor-suppressor genes in many cancers, such as retinoblastoma (Case 39) (see Chapter 15). Many other types of mutations can also lead to a complete loss of function, and all are illustrated by the β-thalassemias (Case 44) (see later discussion), a group of hemoglobinopathies that result from a reduction in the abundance of β-globin, one of the major adult hemoglobin proteins in red blood cells.

The severity of a disease due to loss-of-function mutations generally correlates with the amount of function lost. In many instances, the retention of even a small percent of residual function by the mutant protein greatly reduces the severity of the disease.