Expansion
Silent, missense, nonsense and frameshift, in order of severity
Expansion
Point mutations (substitutions)
- Silent: the codon changes but the amino acid does not, usually at the third base (the wobble position)
- Missense: one amino acid replaced. Severity depends on the residue. Sickle cell disease is the classic example
- Nonsense: creates a premature stop codon, giving a truncated protein. Usually severe. Beta thalassaemia, Duchenne muscular dystrophy
Insertions and deletions
- In frame (multiples of three): one or more amino acids added or lost. Often milder, as in Becker muscular dystrophy and the commonest cystic fibrosis mutation, delta F508
- Frameshift (not a multiple of three): the reading frame shifts, so all downstream codons are misread and a premature stop usually follows. Duchenne muscular dystrophy
Other classes
- Splice site mutations, disrupting intron removal
- Trinucleotide repeat expansions: Huntington disease, fragile X, myotonic dystrophy, Friedreich ataxia. These show anticipation, with earlier and more severe disease in successive generations
The Duchenne and Becker contrast is the clearest illustration of the principle: mutations in the same gene produce very different severity depending on whether the reading frame is preserved.