By Levi Clancy for Student Reader on
Human disease mutations that create nonsense mutations do not always produce a truncated protein. Often they lead to rapid mRNA degradation via Nonsense-Mediated Decay. During splicing in the nucleus, the Exon Junction Complex, containing 4 proteins, is deposited ~20 nt upstream from each exon/exon junction in the final mRNA. This marks the junctions and stays on the RNA as it is transported to the cytoplasm and goes through the first round of translation. The EJC is thought to be displaced from the mRNA during translation.
If translation terminates >50 nt upstream of an EJC, it is not displaced and signals for that mRNA to be degraded. Nonsense mutations generally lead to an early stop codon, so this means that most exonic nonsense mutation will be degraded. The EJC recruits a protein called UPF1 to the mRNA. This in turn stimulates binding of decapping enzymes and deadenylation, leading to rapid degradation. Nonsense mediated decay is advantageous because it prevents the production of truncated and potentially dominant negative mutant proteins in the heterozygous state.
Note that the normal termination codon is almost always in the last exon of a gene. Nonsense mutations in this exon do not lead to nonsense mediated mRNA decay and produce slightly truncated proteins.