While intra-exonic and intronic mutations that affect splicing enhancers could potentially be targeted by AOs, intronic mutations that involve the invariant bases flanking exons are unlikely to be amenable to AO therapy.
Here we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the cumulative loss of dystrophin isoforms, focusing in particular on the risk of cognitive disability for mutations that involve the dystrophin isoform Dp140.
Mutations that involve premature stop-codons or shifted reading frames of the ∼2.5 Mb-long dystrophin gene are primarily responsible for the complete absence of the 427 kDa cytoskeleton protein dystrophin in DMD [3]-[5].
These modifications include mutations that involve domain V of the 23S rRNA and genes encoding riboproteins L4 and L22 (12).
In contrast, glycine is the most limber residue, and thus mutations that involve this amino acid may alter the flexibility of the peptide chain at particular positions.
8, 9 Type II disease is typified by mutations that involve single amino acid substitutions, which are more likely to lead to synthesis of a dysfunctional protein.
This strategy is appropriate for the analysis of SNPs, small insertions and deletions (indels), and mutations that involve only a few bases.
Approximately 50%60%% of cutaneous melanomas harbor BRAF mutations that involve a thymine to adenine DNA base point mutation that replaces the amino acid valine with glutamic acid at the 600 position (BRAF V600E).
A second example of dominant-negative mutations that involve protein misfolding and predispose individuals to disease is the homotetrameric transcription factor p53. Mutations in p53 are one of the most common genetic alterations seen in cancer (Friedman et al., 1993).
Mutations that involve the expression of pseudoexons have been identified in other genes associated with muscular dystrophy including dystrophin 35– 37 and calpain 3. 39, 39 However, in contrast with the present DYSF mutation, these generally lead to frameshifts and premature stop codons that prevent protein expression.
