Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay

摘要: Dominant mutations in the gene encoding mRNA splicing factor PRPF31 cause retinitis pigmentosa, a hereditary form of retinal degeneration. Most these are characterized by DNA changes that lead to premature termination codons. We investigated 6 different mutations, represented single-base substitutions or microdeletions, cell lines derived from 9 patients with dominant pigmentosa. Five codons, and 1 leads skipping exon 2. Allele-specific measurement transcripts revealed strong reduction expression mutant alleles. As consequence, total protein abundance was decreased, no truncated proteins were detected. Subnuclear localization full-length present remained unaffected. Blocking nonsense-mediated decay significantly restored amount but did not restore synthesis proteins, even conjunction inhibitors degradation pathways. Our results indicate most ultimately result null alleles through activation surveillance mechanisms inactivate and, possibly, proteins. Furthermore, data provide compelling evidence pathogenic effect is likely due haploinsufficiency rather than gain function.