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Snapshot: What Are Nonsense Mutations?

Our DNA (deoxyribonucleic acid) serves as a genetic blueprint for building and maintaining our tissues. This complex molecule contains the information needed to build proteins, written in a code made up of four chemical bases: adenine (A), thymine (T), cytosine (C) and guanine (G). During transcription, the DNA sequence—stored in the cell’s nucleus—is copied into another complex molecule called messenger ribonucleic acid (mRNA). This mRNA molecule then serves as a template for protein synthesis, carrying the genetic instructions from the nucleus to cellular machinery called ribosomes, where proteins are assembled.

Sequences of three bases, called codons, specify particular amino acids—the building blocks of proteins. Amino acids are linked together in a specific order to form long chains. These chains fold into proteins, with their complex three-dimensional shapes determined by the amino acid sequence. Click here to learn more about the relationship between DNA, mRNA, amino acids and proteins.

Even small changes in the amino acid sequence can have a dramatic impact on protein structure and function.

Point Mutations

Occasionally, a single chemical base in our DNA is altered, resulting in the coding of an incorrect amino acid and, in turn, atypical protein production. This type of mutation is called a point mutation—the term “point” reflects the specific, isolated nature of the change in the DNA sequence.

Point mutations can be further categorized as missense, nonsense or silent mutations.

Nonsense Mutations - An Abrupt Stop to Protein Production

In a nonsense mutation, the alteration of a single nucleotide base transforms a codon that originally specified a particular amino acid into a stop codon—a molecular signal to stop protein synthesis. By introducing premature stop codons into gene sequences, these mutations lead to the production of shortened, dysfunctional proteins.

For example, in the DNA sequence illustrated below, a nonsense mutation changed the codon TAC, which codes for the amino acid tyrosine (Tyr), into the codon TAG, a stop codon (Stop). Rather than specify a particular amino acid, TAG tells the cellular machinery to halt protein synthesis. The inappropriate placement of a stop codon within this gene sequence results in an incomplete protein that cannot perform its normal roles.

Figure made by Larissa Nitschke using BioRender.org.

Nonsense Mutations and Spinocerebellar Ataxia

Although spinocerebellar ataxia (SCA) is more commonly associated with repeat expansions and missense mutations, nonsense mutations have been identified in several SCA types. One notable example is SCA35, in which nonsense mutations occur in the TGM6 gene. This gene produces transglutaminase 6, a protein critical for maintaining neuronal structure and function in the cerebellum. These nonsense mutations create premature stop signals during protein synthesis, resulting in truncated proteins that do not function properly. The dysfunction of these shortened proteins disrupts cerebellar activity, leading to the characteristic balance and coordination problems seen in ataxia.

If you would like to learn more about nonsense mutations, take a look at these resources by Action Duchenne and the National Human Genome Research Institute.

Written by Dr. Chloe Soutar and edited by Dr. Larissa Nitschke.