Abstract
Mutations in PRPF31 have been implicated in retinitis pigmentosa, a blinding disease caused by degeneration of rod photoreceptors. The disease mechanism in the majority of cases is haploinsufficiency. Crucially, attempts at generation of animal models of disease have proved unsuccessful, yielding animals with a visual phenotype that does not mirror human disease. This suggests that, in these animals, the transcriptional regulation of PRPF31 is different to humans and compared to other species. Study of the evolution of the PRPF31 core promoter has important implications for our understanding of human disease, as disease phenotype is modified by differentially expressed alleles in the population.PRPF31 lies in a head-to-head arrangement with TFPT, a gene involved in cellular apoptosis. The two genes were shown to share common regulatory elements in the human genome. In this study, the core promoters of PRPF31 and TFPT were characterised by dual-luciferase reporter assay using genomic DNA from the green monkey, domestic dog and house mouse. It was found that the core promoters were conserved between human and monkey.In dog, the TFPT core promoter was conserved, but different PRPF31 gene architecture meant the gene was controlled by a long-range promoter lying some 2000bp from the transcription start site.There was very low level of conservation (<20%) of the PRPF31 5′ region between mouse and human. It was shown that mouse populations did not show variable Prpf31 expression levels, revealing a potential explanation for the lack of phenotype observed in the Prpf31 knock-out mouse model.
Highlights
PRPF31 encodes the ubiquitous splicing factor PRPF31, an essential component of the U4/U6.U5 tri-snRNP
Dual luciferase reporter assay was performed and a fragment termed BiP was defined as the core promoter of PRPF31, whereas the core promoter of TFPT was defined as a fragment termed P.31-Luc [15]
The core promoter of the human PRPF31 gene had previously been identified as Bi-P, the region at chr19:54618440-54619393 and the TFPT promoter was contained within this region [15]
Summary
PRPF31 encodes the ubiquitous splicing factor PRPF31, an essential component of the U4/U6.U5 tri-snRNP. Mutations in PRPF31 have been shown to be a major cause of autosomal dominant retinitis pigmentosa (adRP), accounting for 5% of disease in the UK [1,2]. A unique feature of PRPF31-associated adRP is phenotypic nonpenetrance, where within affected families there are asymptomatic mutation carriers. This is due to the existence of differentially expressed wildtype PRPF31 alleles, with co-inheritance of a PRPF31 mutation and a higher-expressing allele providing protection against clinical manifestation of disease. It has been shown that there is variable expression of PRPF31 in the general population and, that within mutation carrying families, asymptomatic mutation carriers have more than two-fold higher expression levels of wildtype PRPF31 compared to symptomatic individuals [3,4,5,6]
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