Missense Mutation

A missense, or nonsynonymous, mutation is a type of point mutation affecting the coding region of a gene which alters a single base such that it codes for a different amino acid. The effects of such a change may be a profound change in phenotype, no perceptible change in phenotype, or some intermediate effect. When the effect of a missense mutation shows no significant phenotypic change, it is often termed neutral or quiet by analogy to so-called silent mutations where the point mutation does not alter the amino acid sequence of the encoded protein at all.

Overall, missense mutations are reported to account for approximately half of the mutations causing genetic disorders in humans. Among diseases specifically affecting the metabolic activity of mitochondria, missense mutations are, by far, the most prevalent form of point mutation to mitochondrial DNA.

The classic example of a missense mutation with profound effect is sickle cell disease where a change in a single base of the 17th codon of the beta-subunit changes one amino acid in the beta-subunit giving rise to the disease phenotype. However, a fuller understanding of the implications of missense mutations comes from the study of enzyme function.

The X-linked hypoxanthine guanine phosphoribosyl transferase (HGPRT) gene is crucial for nucleic acid metabolism. Missense mutations to HGPRT create a variety of disease states depending on the exact location of the mutation and significance of the difference in amino acid caused by the mutation. The extent of residual enzyme activity in mutants correlates well with the clinical phenotype of affected males. Considerations in the interpretation of such mutations include whether the location of the mutation will alter a portion of the enzyme actively involved in chemical reactions and whether the new amino acid is sufficiently similar in both size and chemical properties to allow the resulting protein to conform to a functional shape.