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 in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation where a single nucleotide is changed to cause substitution of a different amino acid. Some genetic disorders, such as thalassemia and DMD, result from nonsense mutations.
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 was 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-then-translated as UGA, the resulting transcript and protein product would be:
DNA: 5' - ATG ACT CAC TGA GCG CGA AGC TGA - 3' 3' - TAC TGA GTG ACT CGC GCT TCG ACT - 5' mRNA: 5' - AUG ACU CAC UGA GCG CGU AGC UGA - 3' Protein: Met Thr His Stop
The remaining codons of the mRNA are not translated into amino proteins 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.
The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. “Amber” was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means “amber” in German. The other two stop codons were named “ochre” and “opal” in order to keep the “color names” theme. Stop codons are also called “termination”or “nonsense” codons. They signal release of the nascent polypeptide from the ribosome because there is no cognate tRNA that has anticodons complementary to these stop signals, and so a release factor binds to the ribosome instead.
Pathology associated with nonsense mutations
Nonsense mutations can cause a genetic disease by damaging a gene responsible for a specific protein, for example, dystrophin 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 the G542X mutation in the cystic fibrosis transmembrane conductance regulator gene).
- Duchenne muscular dystrophy (dystrophin)
- Beta thalassaemia (β-globin)
- 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 was scheduled to enter the final phase of clinical trials in 2007.
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