Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa.

Détails

Ressource 1Télécharger: BIB_5D1C3976F501.P001.pdf (913.07 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_5D1C3976F501
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa.
Périodique
Scientific reports
Auteur(s)
Rose A.M., Shah A.Z., Venturini G., Krishna A., Chakravarti A., Rivolta C., Bhattacharya S.S.
ISSN
2045-2322 (Electronic)
ISSN-L
2045-2322
Statut éditorial
Publié
Date de publication
19/01/2016
Peer-reviewed
Oui
Volume
6
Pages
19450
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Résumé
PRPF31-associated retinitis pigmentosa presents a fascinating enigma: some mutation carriers are blind, while others are asymptomatic. We identify the major molecular cause of this incomplete penetrance through three cardinal features: (1) there is population variation in the number (3 or 4) of a minisatellite repeat element (MSR1) adjacent to the PRPF31 core promoter; (2) in vitro, 3-copies of the MSR1 element can repress gene transcription by 50 to 115-fold; (3) the higher-expressing 4-copy allele is not observed among symptomatic PRPF31 mutation carriers and correlates with the rate of asymptomatic carriers in different populations. Thus, a linked transcriptional modifier decreases PRPF31 gene expression that leads to haploinsufficiency. This result, taken with other identified risk alleles, allows precise genetic counseling for the first time. We also demonstrate that across the human genome, the presence of MSR1 repeats in the promoters or first introns of genes is associated with greater population variability in gene expression indicating that copy number variation of MSR1s is a generic controller of gene expression and promises to provide new insights into our understanding of gene expression regulation.

Mots-clé
Alleles, Binding Sites, Conserved Sequence, DNA Copy Number Variations, Eye Proteins/metabolism, Gene Expression, Gene Expression Regulation, Gene Frequency, Genes, Reporter, Genetics, Population, Genotype, Humans, Nucleotide Motifs, Penetrance, Phenotype, Position-Specific Scoring Matrices, Promoter Regions, Genetic, Repetitive Sequences, Nucleic Acid, Retinitis Pigmentosa/genetics, Retinitis Pigmentosa/metabolism, Scavenger Receptors, Class A/genetics, Transcription, Genetic
Pubmed
Open Access
Oui
Création de la notice
07/02/2016 18:36
Dernière modification de la notice
20/08/2019 15:15
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