*4.7. Class 5 Mutations*

The next group of mutations consists of those that cause diminished protein expression (Class 5). Class 1 and Class 5 mutations differ from one another in respect of that the former results in no protein expression, whereas the latter only cause reduced protein levels, therefore, different strategies are required for rescuing the phenotype. A representative of this group is T153M (rs199753603), which leads to diminished protein expression, but the smaller amount of protein expressed normally traffics to the cell surface and functions regularly [104,107,128,133].

Although we focus here mostly on the mutations in the coding region, it is worth mentioning that SNPs in the promoter region or in introns (potentially causing alternative splicing) can influence RNA stability and consequently lead to diminished protein expression. These are exemplified by −30477C>G (rs2127861), −15622C>T (rs7699188), and 1143G>A (rs2622604) [134]. Since the transcriptional regulation and RNA splicing is tissue-specific, the manifestation of these SNPs can vary from tissue to tissue. It is noteworthy that correction of aberrant splicing by RNA-based antisense oligonucleotide strategy has been proposed to restore CFTR level caused by splice-altering mutations [139].
