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CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance.

Venturini, G; Rose, AM; Shah, AZ; Bhattacharya, SS; Rivolta, C; (2012) CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance. PLoS Genet , 8 (11) , Article e1003040. 10.1371/journal.pgen.1003040. Green open access

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Abstract

Heterozygous mutations in the PRPF31 gene cause autosomal dominant retinitis pigmentosa (adRP), a hereditary disorder leading to progressive blindness. In some cases, such mutations display incomplete penetrance, implying that certain carriers develop retinal degeneration while others have no symptoms at all. Asymptomatic carriers are protected from the disease by a higher than average expression of the PRPF31 allele that is not mutated, mainly through the action of an unknown modifier gene mapping to chromosome 19q13.4. We investigated a large family with adRP segregating an 11-bp deletion in PRPF31. The analysis of cell lines derived from asymptomatic and affected individuals revealed that the expression of only one gene among a number of candidates within the 19q13.4 interval significantly correlated with that of PRPF31, both at the mRNA and protein levels, and according to an inverse relationship. This gene was CNOT3, encoding a subunit of the Ccr4-not transcription complex. In cultured cells, siRNA-mediated silencing of CNOT3 provoked an increase in PRPF31 expression, confirming a repressive nature of CNOT3 on PRPF31. Furthermore, chromatin immunoprecipitation revealed that CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression. In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31 transcripts to be produced and preventing manifestation of retinal degeneration.

Type: Article
Title: CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1003040
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1003040
Language: English
Additional information: Copyright: © 2012 Venturini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Swiss National Science Foundation (grants 320030-121929 and 310030_138346), the Gebert Rüf Foundation (Rare Diseases - New Technologies grant), the Rosetrees Trust, and Fight for Sight. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: Eye Proteins, Gene Expression Regulation, Heterozygote, Humans, Penetrance, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Small Interfering, Retinitis Pigmentosa, Sequence Deletion, Transcription Factors
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1378584
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