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PRPF31, a gene located at chromosome 19q13.4, encodes the ubiquitous splicing factor PRPF31. The gene lies in a head-to-head arrangement with TFPT, a poorly characterized gene with a role in cellular apoptosis. Mutations in PRPF31 have been implicated in autosomal dominant retinitis pigmentosa (adRP), a frequent and important cause of blindness worldwide. Disease associated with PRPF31 mutations is unusual, in that there is often non-penetrance of the disease phenotype in affected families, caused by differential expression of PRPF31. This study aimed to characterize the basic promoter elements of PRPF31 and TFPT. Luciferase reporter constructs were made, using genomic DNA from an asymptomatic individual with a heterozygous deletion of the entire putative promoter region. Fragments were tested by the dual-luciferase reporter assay in HeLa and RPE-1 cell lines. A comparison was made between the promoter regions of symptomatic and asymptomatic mutation-carrying individuals. A patient (CAN493) with adRP was identified, harbouring a regulatory region mutation; both alleles were assayed by the dual-luciferase reporter assay. Luciferase assays led to the identification of core promoters for both PRPF31 and TFPT; despite their shared gene architecture, the two genes appear to be controlled by slightly different regulatory regions. One functional polymorphism was identified in the PRPF31 promoter that increased transcriptional activation. The change was not, however, consistent with the observed symptomatic-asymptomatic phenotypes in a family affected by PRPF31-adRP. Analysis of the mutant promoter fragment from CAN493 showed a >50% reduction in promoter activity, suggesting a disease mechanism of functional haploinsufficiency-the first report of this disease mechanism in adRP.

Original publication




Journal article


Human molecular genetics

Publication Date





4126 - 4137


Department of Genetics, UCL Institute of Ophthalmology, London EC1V 9EL, UK.


Hela Cells, Humans, Retinitis Pigmentosa, Eye Proteins, Luciferases, Renilla, Statistics, Nonparametric, Case-Control Studies, Cloning, Molecular, DNA Mutational Analysis, Phylogeny, Transcription, Genetic, Gene Expression Regulation, Sequence Deletion, Base Sequence, Conserved Sequence, Genes, Dominant, Polymorphism, Single Nucleotide, Genes, Reporter, Molecular Sequence Data, Aged, Female, Male, Basic Helix-Loop-Helix Transcription Factors, Promoter Regions, Genetic, Genetic Association Studies