Nonsense mutation

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and possibly a truncated, and often nonfunctional protein product.

Simple example

For example, given the following sense DNA sequence, the corresponding mRNA transcript, and the translated protein product:

    DNA: 5' - ATG ACT CAC CGA GCG CGA AGC TGA - 3'
         3' - TAC TGA GTG GCT CGC GCT TCG ACT - 5'
   mRNA: 5' - AUG ACU CAC CGA GCG CGA AGC UGA - 3'
Protein:      Met Thr His Arg Ala Arg Ser Stop

Suppose that a nonsense mutation were introduced at the fourth triplet in the DNA sequence (CGA) causing the cytosine to be replaced with thymine, yielding TGA in the DNA sequence. Since TGA is transcribed as UGA, the resulting transcript and protein product would be:

   mRNA: 5' - AUG ACU CAC UGA CGC CGU AGC UGA - 3'
Protein:      Met Thr His Stop

The remaining codons of the mRNA are not translated into amino acids because the stop codon is prematurely reached during translation. This can yield a truncated abbreviated protein product, which quite often lacks the functionality of the normal, non-mutant protein.

Nonsense-mediated mRNA decay

Despite an expected tendency for premature termination codons to yield shortened polypeptide products, in fact the formation of truncated proteins does not occur often in vivo. Many organisms -- including humans and lower species, such as yeast -- employ a nonsense-mediated mRNA decay pathway, which degrades mRNAs containing nonsense mutations before they are translated into nonfunctional polypeptides.

Pathology associated with nonsense mutations

Nonsense mutations can cause a genetic disease by damaging a gene responsible for a specific protein, for example, distrophin in Duchenne muscular dystrophy. The same disease may, however, be caused by other kinds of damage to the same gene. Examples of diseases in which nonsense mutations are known to be among the causes include:

• Cystic fibrosis (caused by mutations in the cystic fibrosis transmembrane conductance regulator gene).
• Duchenne muscular dystrophy (distrophin)
• Beta thalassaemia
• Hurler syndrome

An experimental drug known as PTC124 may be useful in treating some cases of each of the above diseases (that is, the cases caused by a nonsense mutation). PTC124 is scheduled to enter the final phase of clinical trials in 2007.^[1]

External links and references

1. ^ Daily pill to beat genetic diseases - Times Online. Retrieved on 2007-10-23.

• Mutations
• Nonsense mutation (Medical dictionary)
• Gatfield D, Unterholzner L, Ciccarelli FD, Bork P, Izaurralde E., "Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways". EMBO J. 2003 Aug 1;22(15):3960-70. PMID 12881430
• Welch EM, et al., "PTC124 targets genetic disorders caused by nonsense mutations", Nature 447, 87-91 (3 May 2007) (DOI: 10.1038/nature05756)