A Study into the Evolutionary Divergence of the Core Promoter Elements ofPRPF31andTFPT.
Mutations inPRPF31have 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 ofPRPF31is different to humans and compared to other species. Study of the evolution of thePRPF31core promoter has important implications for our understanding of human disease, as disease phenotype is modified by differentially expressed alleles in the population.PRPF31lies in a head-to-head arrangement withTFPT, 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 ofPRPF31andTFPTwere 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, theTFPTcore promoter was conserved, but differentPRPF31gene 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 thePRPF315' region between mouse and human. It was shown that mouse populations did not show variablePrpf31expression levels, revealing a potential explanation for the lack of phenotype observed in thePrpf31knock-out mouse model.
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Anna M
AM
Rose
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Amna Z
AZ
Shah
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Giovanna
G
Alfano
Ocular Genomics Institute & Berman-Gund Laboratory, Department of Ophthalmology, Harvard Medical School, Boston, USA.
Kinga M
KM
Bujakowska
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Amy F
AF
Barker
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
J Louis
JL
Robertson
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Sufia
S
Rahman
Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, 41092, Spain.
Lourdes Valdés
LV
Sánchez
Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, 41092, Spain.
Francisco J
FJ
Diaz-Corrales
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Christina F
CF
Chakarova
Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER), Seville, 41092, Spain.
Abhay
A
Krishna
Department of Genetics, UCL Institute of Ophthalmology, London, United Kingdom.
Shomi S
SS
Bhattacharya
Dual-luciferase reporter; PRPF31 mutation; Photoreceptor; TFPT