Nonsense and Frameshift Mutations

Nonsense and frameshift mutations both tend to truncate a protein. A nonsense mutation converts a codon for an amino acid into a premature stop codon, while a frameshift, caused by inserting or deleting a number of bases not divisible by three, shifts the reading frame so that downstream codons are misread and a premature stop is usually reached. Both are common mechanisms of loss-of-function in genetic disease.

Definition

A nonsense mutation is a change that converts a sense codon into a stop codon, prematurely terminating translation; a frameshift mutation is an insertion or deletion of a number of nucleotides not a multiple of three, which shifts the downstream reading frame and typically produces a premature stop codon.

Scope

This topic covers two truncating mechanisms: nonsense substitutions that introduce a premature termination codon, and small insertions or deletions that shift the translational reading frame. It addresses their shared downstream consequence — premature termination, often followed by nonsense-mediated decay of the transcript — and how truncating variants are interpreted. It is a reference entry, not clinical guidance; single-base substitutions that preserve the frame are covered under point mutations.

Key concepts

• Premature termination codon
• Reading frame
• Insertion/deletion (indel)
• Nonsense-mediated mRNA decay (NMD)
• Loss of function
• Truncating variant
• Haploinsufficiency

Mechanisms

A nonsense mutation creates a premature termination codon directly through a base substitution. A frameshift arises when an insertion or deletion whose length is not a multiple of three alters the grouping of nucleotides into codons, so that everything downstream is read in a different frame and a stop codon is usually encountered soon after. In both cases the result is often a truncated or non-functional protein. Many transcripts bearing a premature termination codon are recognised and degraded by nonsense-mediated mRNA decay (NMD), a surveillance pathway that reduces production of potentially harmful truncated proteins (Kervestin & Jacobson, 2012). Whether NMD acts depends on the position of the premature stop relative to features such as the last exon-exon junction, which influences whether a truncating variant causes loss of function or a residual altered product.

Clinical relevance

Nonsense and frameshift variants are frequently classified as likely loss-of-function and, in genes where loss of function is an established disease mechanism, carry strong weight toward pathogenicity in interpretation frameworks. Their effect can be modulated by NMD and by the position of the change within the gene. This topic describes how such variants are recognised, named, and weighed and is not a basis for individual diagnostic or treatment decisions.

Evidence & guidelines

The ACMG/AMP framework (Richards et al., 2015) treats predicted null variants (including nonsense and frameshift changes) as strong evidence toward pathogenicity in genes where loss of function is a known mechanism, with caveats about variant position and NMD; HGVS nomenclature (den Dunnen et al., 2016) standardises how these changes are described.

Debates

Do all truncating variants behave as null alleles?

Truncating variants near the 3' end of a gene, in the last exon, or in transcripts that escape nonsense-mediated decay may yield a partly functional or stable truncated protein rather than complete loss of function, so the position of the premature stop matters for interpretation.

Seminal works

• kervestin-2012
• richards-2015

Frequently asked questions

Why does a frameshift usually create a premature stop codon?

Shifting the reading frame changes how all downstream nucleotides are grouped into codons, producing an essentially random new sequence in which one of the three stop codons is typically encountered within a short distance.

What is nonsense-mediated decay?

It is a cellular surveillance pathway that detects messenger RNAs carrying a premature termination codon and degrades them, reducing the production of truncated proteins and thereby influencing the consequence of nonsense and frameshift variants.