Nonsense mutation

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. As nonsense mutations lead to premature termination of polypeptide chains, they are also called chain termination mutations.

Missense mutations differ from nonsense mutations since they are point mutations that exhibit a single nucleotide change to cause substitution of a different amino acid. A nonsense mutation also differs from a nonstop mutation, which is a point mutation that removes a stop codon. About 10% of patients facing genetic diseases have involvement with nonsense mutations. Some of the diseases that these mutations can cause are Duchenne muscular dystrophy (DMD), cystic fibrosis (CF), spinal muscular atrophy (SMA), cancers, metabolic diseases, and neurologic disorders. The rate of nonsense mutations is variable from gene-to-gene and tissue-to-tissue, but gene silencing occurs in every patient with a nonsense mutation. For example, a nonsense mutation occurring in a gene encoding a protein can cause structural or functional defects in the protein that disrupt cellular biology. Depending on the significance of the functions of this protein, this disruption could be detrimental to the fitness and survival of that organism.]]

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 able to be translated into nonfunctional polypeptides.

tRNA Suppression

Because nonsense mutations result in altered mRNA with a premature stop codon, one way of suppressing the damage done to the final protein's function is to alter the tRNA that reads the mRNA. These tRNA’s are termed suppressor tRNA's. If the stop codon is UAG, any other amino acid tRNA could be altered from its original anticodon to AUC so it will recognize the UAG codon instead. This will result in the protein not being truncated, but it may still have an altered amino acid. These suppressor tRNA mutations are only possible if the cell has more than one tRNA that reads a particular codon, otherwise the mutation would kill the cell. The only stop codons are UAG, UAA, and UGA. UAG and UAA suppressors read their respective stop codons instead of their original codon, but UAA suppressors also read UAG due to wobble base pairing. UGA suppressors are very rare. Another hurdle to pass in this technique is the fact that stop codons are also recognized by release factors, so the tRNA still needs to compete with the release factors to keep the translation going. Because of this, suppression is usually only 10-40% successful. These suppressor tRNA mutations also target stop codons that are not mutations, causing some proteins to be much longer than they should be. Only bacteria and lower eukaryotes can survive with these mutations, mammal and insect cells die as a result of a suppressor mutation.

Common disease-associated nonsense mutations

thumb|300x300px|Selection of notable mutations, ordered in a standard table of the [[genetic code of amino acids. nonsense mutations are marked by red arrows.]]

Nonsense mutations comprise around 20% of single nucleotide substitutions within protein coding sequences that result in human disease. Nonsense mutation-mediated pathology is often attributed to reduced amounts of full-length protein, because only 5-25% of transcripts possessing nonsense mutations do not undergo nonsense-mediated decay (NMD).

Twenty-three different single-point nucleotide substitutions are capable of converting a non-stop codon into a stop-codon, with the mutations CGA<math>\longrightarrow</math>TGA and CAG<math>\longrightarrow</math>TAG being the most common disease-related substitutions characterized in the Human Gene Mutation Database (HGMD). Sequences surrounding the stop codon also impact termination efficiency. The pulmonary system relies on SMAD1, SMAD5, and SMAD 8 to regulate pulmonary vascular function. Downregulation and loss of signals that are normally operated by SMAD8 contributed to pathogenesis in pulmonary arterial hypertension. Wnt signaling regulates bone mass and osteoblast differentiation and is important for the development of bone, heart, and muscle.

Antisense oligonucleotides to suppress the expression of NMD and translation termination proteins are being explored in animal models of nonsense mutation-induced disease. Other RNA therapeutics under investigation include synthetic suppressor tRNAs that enable ribosomes to insert an amino acid, instead of initiating chain termination, upon encountering premature stop codons.

Read-through has been achieved using small molecule drugs such as aminoglycosides and negamycin. Ataluren, sold under the tradename Translarna, is currently an approved treatment for Duchenne muscular dystrophy in the European Economic area and Brazil. However, phase III trials of Ataluren as a cystic fibrosis therapeutic have failed to meet their primary endpoints.

Nonsense mutation

Common disease-associated nonsense mutations

See also

External links and references