There appears to be a high percentage of mutations that lead to gross deletion in PRPF31. In this report, five of six
PRPF31 mutations identified lead to premature termination of PRPF31, due to exon skipping, insertion of additional amino acids, or a premature stop codon. This observation is consistent with all the previously reported
PRPF31 mutations, 7 of 9 reported by Vithana et al.,
2 3 of 3 by Martinez-Gimeno et al.
10 and Sato et al.,
13 and 9 of 11 by Sullivan et al..
11 These results could be an underestimation as any large deletion, insertion, duplication, and inversion will be missed by the present screening procedures which only screen the exons along with adjacent intronic sequences. Furthermore, it has been estimated that at least 15% of point mutations exert their effect on the standard consensus intronic splice sites, resulting in exon skipping, or less commonly, in the creation of an ectopic splice site or activation of a cryptic splice site.
14 This has recently been shown for the missense mutation p.Leu107Val in
PRPF31.
15 This change creates a new splice site that results in a 4-bp deletion in exon 4 resulting in a frameshift and premature termination of the resultant protein. A single missense mutation identified in this study, C412A, also appears to create a weak splice donor site. The splice site prediction program NetGene2 (http://www.cbs.dtu.dk/databases/ provided in the public domain by the Center for the Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark) shows that C412A appears to create a splice donor site, TCCGCAAGGTCAAGGT, (confidence increases from 0 to 0.55) that results in the deletion of 6 bp at the end of exon 5. Taken together, these results suggest that haploinsufficiency, rather than the dominant negative affect of the mutant protein, appear to be the cause of disease in patients with adRP, due to
PRPF31 mutations. This conclusion is also consistent with the fact that there is a reduction of
PRPF31 mRNA derived from mutant alleles,
15 most likely due to nonsense-mediated decay, which can be triggered by transcripts bearing premature translation termination codons.