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Synonymous nucleotide substitutions may not be "silent".

Single nucleotide substitutions that are located within an exon but which do not change the encoded amino acid i.e. "synonymous mutations", were previously regarded as non-pathogenic. There are, however, at least two mechanisms that are now recognised by which such nucleotide changes may in fact have significant damaging effects.
 
The first is the situation in which a nucleotide that is changed lies within a particular short sequence that assists in splicing by binding to protein factors. These sequences can lie within exons and are known as Exonic Splice Enhancer (ESE) sequences. Mutations that are located in an ESE may not change the amino acid sequence but can result in altered splicing with for example, intron retention or exon skipping.
 
A second mechanism has been reported recently in Science. Researchers investigating different actin genes found slight differences in the nucleotide sequence between beta and gamma actin genes that did not alter the amino acid sequence but nevertheless did result in significant functional consequences. Specifically, they found that the slightly different nucleotide sequence, by causing different codon usage, slowed the rate of translation of the protein. This, in turn, slowed the rate of protein folding and, as a result, allowed time for ubiquitination (of a normally internal lysine amino acid) to take place, thus causing accelerated degradation of the protein in the intracellular organelles named proteasomes. Thus, the nucleotide substitution, although not affecting the protein's primary structure (amino acid sequence) was having an effect upon its rate of translation and, consequently, its post-translational modification and stability.
 
 
 
 
For a summary article, see:
 
and, for the detailed research paper, see:
 
Source: Science. 
 
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