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

Détails

ID Serval
serval:BIB_28E4A9D5B592
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay.
Périodique
Journal of Clinical Investigation
Auteur⸱e⸱s
Rio Frio T., Wade N.M., Ransijn A., Berson E.L., Beckmann J.S., Rivolta C.
ISSN
0021-9738 (Print)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
2008
Peer-reviewed
Oui
Volume
118
Numéro
4
Pages
1519-1531
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
Dominant mutations in the gene encoding the mRNA splicing factor PRPF31 cause retinitis pigmentosa, a hereditary form of retinal degeneration. Most of these mutations are characterized by DNA changes that lead to premature termination codons. We investigated 6 different PRPF31 mutations, represented by single-base substitutions or microdeletions, in cell lines derived from 9 patients with dominant retinitis pigmentosa. Five of these mutations lead to premature termination codons, and 1 leads to the skipping of exon 2. Allele-specific measurement of PRPF31 transcripts revealed a strong reduction in the expression of mutant alleles. As a consequence, total PRPF31 protein abundance was decreased, and no truncated proteins were detected. Subnuclear localization of the full-length PRPF31 that was present remained unaffected. Blocking nonsense-mediated mRNA decay significantly restored the amount of mutant PRPF31 mRNA but did not restore the synthesis of mutant proteins, even in conjunction with inhibitors of protein degradation pathways. Our results indicate that most PRPF31 mutations ultimately result in null alleles through the activation of surveillance mechanisms that inactivate mutant mRNA and, possibly, proteins. Furthermore, these data provide compelling evidence that the pathogenic effect of PRPF31 mutations is likely due to haploinsufficiency rather than to gain of function.
Mots-clé
Adult, Alleles, Cell Line, Codon, Nonsense/genetics, Eye Proteins/genetics, Eye Proteins/metabolism, Female, Gene Expression Regulation, Haplotypes, Humans, Male, Middle Aged, Mutation/genetics, Protein Transport, RNA, Messenger/genetics, RNA, Messenger/metabolism, Retinitis Pigmentosa/genetics, Retinitis Pigmentosa/metabolism, Transcription, Genetic/genetics
Pubmed
Web of science
Open Access
Oui
Création de la notice
06/08/2008 18:14
Dernière modification de la notice
20/08/2019 14:08
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