Nonsense Mutations
A nonsense mutation is a change in the polynucleotide sequence that results in the production of a protein chain terminating codon that prematurely stops protein synthesis during the process of translation. As a result of a nonsense mutation, instead of the insertion of the proper amino acid into the chain of amino acids bonded together to form a protein, the synthesis of the protein prematurely stops. Unless there is another mutation in a gene that codes for a transfer RNA (tRNA) that allows the suppression of a nonsense mutation, a premature termination of protein synthesis results in the manufacture and release of an incomplete (truncated) and usually nonfunctional protein fragment.
A mutation is a change in a gene or chromosome. There are many types of mutations, including those resulting in a substitution of bases in the DNA sequence (i.e., one nucleotide is exchanged for another in the polynucleotide sequence. The effects of these mutations depend on the type, extent, and placement of the mutation in the DNA sequence. The effects of mutations range from silent mutations that do not result in a change in the translated protein sequence to mutations that are lethal and prevent embryonic development.
A change (e.g., a point mutation) in the polynucleotide strand of DNA can result in an alteration of the sequence of three bases in the messenger ribonucleic acid (mRNA). When the change results in a nonsense mutation, the mRNA codon that normally relays the instruction to insert a specific amino acid in the lengthening amino acid chain during protein synthesis, instead orders the termination of protein synthesis.
For example, a nonsense mutation in the beta chain of hemoglobin, can result in hemoglobin (Hb) thalassemia (a general clinical term for a range of conditions in which amount of hemoglobin produced is less than normal). One particular form of Hb thalassemia can result from a nonsense mutation that produces an amber codon (chain termination codon) at a place in the codon sequence that normally carries the instruction to insert the amino acid lysine in the beta hemoglobin chain synthesized during translation.
Amber, ocher and opal mutations are types of nonsense mutations. An amber mutation in DNA results in the creation of a UAG (uracil-adenine-guanine) sequence codon (amber codon). Amber mutations result from any change in a strand of DNA that results in the creation of a UAG sequence codon in mRNA. An ocher mutation results in the creation of a UAA (uracil-adenine-adenine) mRNA codon (ocher codon). An opal mutation results in the production of a UGA codon sequence (umber or opal codon).
For example, if the base sequence of the coding stand of DNA is CAG, because of restricted base paring (e.g., A-T and C-G) the anticoding DNA strand used as a transcription template contains a GTC sequence. Because uracil (U) replaces thymine in mRNA, the DNA coding strand sequence (the strand that has the same sequence as does the mRNA transcript) results in a mRNA codon sequence of CAG. This codon sequence is ultimately translated to insert the amino acid glutamine (Gln) into the translated protein's sequence of amino acids. A point mutation resulting in the substitution of thymine (T) for cytosine (C) at the start of the coding strand sequence results in an amber nonsense mutation (i.e., a DNA sequence of TAG that results in an UAG amber codon in the mRNA). As a result of this particular nonsense mutation, instead inserting the amino acid glutamine into the lengthening amino acid chain during the translation process, the instruction is interpreted as a stop command and the synthesis of the protein is terminated.
Nonsense mutation suppressors are mutant genes that result in the production of transfer ribonucleic acids (tRNA) that have anticodons altered so that they have the ability to read through codons produced by nonsense mutations. Nonsense suppressors allow the continued synthesis of the protein. Accordingly, although the amino acid sequence is altered and the substitution of a different amino acid in the protein chain may result in changes in the shape or functioning of the protein, the suppression of the nonsense mutation allows the process of protein synthesis to continue uninterrupted.
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