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Title: Transcriptional regulation of PRPF31 gene expression by MSR1 repeat elements causes incomplete penetrance in retinitis pigmentosa.
Authors: Rose, Anna M
Shah, Amna Z
Venturini, Giulia
Krishna, Abhay
Chakravarti, Aravinda
Rivolta, Carlo
Bhattacharya, Shomi S
metadata.dc.subject.mesh: Alleles
Binding Sites
Conserved Sequence
DNA Copy Number Variations
Eye Proteins
Gene Expression
Gene Expression Regulation
Gene Frequency
Genes, Reporter
Genetics, Population
Nucleotide Motifs
Position-Specific Scoring Matrices
Promoter Regions, Genetic
Repetitive Sequences, Nucleic Acid
Retinitis Pigmentosa
Scavenger Receptors, Class A
Transcription, Genetic
Issue Date: 19-Jan-2016
Abstract: 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.
metadata.dc.identifier.doi: 10.1038/srep19450
Appears in Collections:Producción 2020

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