Figure 5.

DNA sequence in wild type (WT), in III/1 heterozygote carrier mother, in IV/1 and III/2 hemizygote patients. In case of patients with c.78+1G→C mutation there may be two possible ways during RNA splicing. The first possible way is the partial intron retention by the activation of a cryptic splice site. Mutating the conserved splice donor site from GT to CT, a novel cryptic site may become activated during RNA splicing, and thus the splice is probably shifted by ten nucleotides (CTA TGT AAC A) downstream to the next GT in the intronic sequence. Thus exon 2 gets longer by 10 nucleotides (marked blue in the picture), which results in a frameshift and finally cause a premature termination codon (PTC) at the beginning of exons 3 (after codon 30). In this way the truncated RS1 protein would contain only 30 AAs, but previously the truncated mRNA may probably be eliminated by the nonsense-mediated mRNA decay (NMD). The second possible way is the exon 2 skipping with a 26 bp deletion (marked blue in the picture) at position 52. It may result in a frameshift and a new PTC at the beginning of exon 3 at the same position like in case the above described partial intron retention. In this way the truncated RS1 protein would consist of only 17 AAs and an additional new one (marked green in the picture) at the C terminal. But previously, like in the first hypothetical way, the truncated mRNA may probably be eliminated by the nonsense-mediated mRNA decay resulting in no functional RS1 protein.