Nonsense Mutation

Normally, messenger ribonucleic acid (mRNA) translation to protein is terminated by one of three stop codons. A point mutation that converts a codon for a normal amino acid into a stop codon is called a nonsense mutation. The new, premature, stop codon is often termed a nonsense codon to highlight the true effect of such mutations: the creation of nonsensical mRNA transcripts which translate into proteins that are typically nonfunctional. Contrast this with a normally located stop codon which properly regulates the length of proteins created from an mRNA transcript.

In general, such mutations do not alter the activity of transcription (which is terminated by mechanisms distinct from the stop codon). However, mRNA transcripts containing nonsense mutations are usually highly unstable and decay before translation can occur.

This evolutionarily advantageous mechanism helps cells conserve resources by not expending energy on the production of proteins with limited, nonexistent, [Page 1249]or malignant functionality. If mRNA with a nonsense mutation happens to be translated into a protein sequence, the protein itself is often so unstable that it is targeted by the cell for destruction.

While the complete abolition of protein function caused by such mutations would seem to make them good candidates for disease causation, they make up only 12 percent of all disease causing mutants. The most likely explanation for this is that the complete loss of protein function is often incompatible with life, meaning very few children are born with such mutations. Furthermore, many of those who develop such mutations spontaneously in adulthood likely never develop disease because the complete abolition of certain protein functions so radically alters homeostasis on a cellular level that programmed cell death is initiated, limiting the potential for such a mutation to cause disease.