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Investigating the molecular basis of partial penetrance with splicing factor gene, PRPF31, implicated in Retinitis Pigmentosa

Veraitch, B.K.; (2008) Investigating the molecular basis of partial penetrance with splicing factor gene, PRPF31, implicated in Retinitis Pigmentosa. Doctoral thesis , UCL (University College London).

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Retinitis Pigmentosa (RP, MIM#268000) is a significant cause of blindness in the Western world with an incidence of 1 in 3500. The mode of inheritance in RP may be autosomal recessive (ar), autosomal dominant (ad), X-linked recessive or digenic. To date, 39 loci have been implicated in RP, of which 30 genes are known (http://www.sph.uth.tmc.edu/Retnet/home.htm). Three recently identified pre-mRNA splicing factors, PRPF31, PRPF8, and PRPF3 correspond to RP11, 13, and 18, respectively. Our ongoing research on the genetic basis of RP resulted in the mapping of an autosomal dominant RP (adRP) locus on chromosome 19q13.4 (RP11). The genetic interval was refined to a 520kb region flanked by markers D19S927 and D19S781.2 Mutation screening led to the exciting discovery of splicing factor gene, PRPF31, implicated in RP11. The unique feature associated with this locus has been the consistent finding of partial penetrance phenotype in most RP11 families worldwide. The molecular mechanism responsible for this feature still remains unclear. We speculated that the reason for partial penetrance is due to the different levels of expression of the normal copy of the gene that is able to compensate for that mutant allele is asymptomatic individuals (or unable to in the symptomatic individuals). Partial penetrance can be viewed as nature’s way of curing the disease. Though our recent studies we demonstrated that symptomatic and asymptomatic individuals in a given sib-ship consistently inherited different wild-type (WT) alleles of pRPF from their unaffected parent. This resulted in the asymptomatics having higher levels of WT PRPF31 mRNA compared to symptomatic individuals. We feel this might explain the partial penetrance phenotype observed in most RP11 families. The aim of the thesis is to explore the molecular mechanism that underlies the partial penetrance phenotype associated with the PRPF31 gene, causing adRP. For this reason, the variation in the wild-type PRPF31 expression level was assessed in random unrelated individuals, at the mRNA level and protein level. From the data generated, it showed that in the general population there are individuals with two high expressing alleles (HH), individuals with one high and one low (HL) and others who have two low expressing alleles (LL), suggesting a continuous spectrum with three overlapping (high, intermediate and low) levels of PRPF31 expression. In order to identify the novel sequence change in PRPF31 gene, responsible for the differential expression of PRPF31 alleles, the ~520kb region spanning PRPF31 gene has been targeted to be amplified and sequenced, where the genetic change might exist. A SNP rs460824 located #93 kb (based on the standard ENSEMBL database) upstream of PRPF31 showed significant association (chi square 7.5, P<0.01) in a RP11 family. This particular SNP analysis highlighted the fact that there could be other SNPs across the 520kb interval which may act in combination to up-regulate or down-regulate the transcriptional activity. In addition, the presence of copy number variation at the RP11 locus was also investigated to identify as a cause for the differential expression of PRPF31. Comparative genomic hybridization (CGH) tiling array and real time quantitative PCR study revealed a difference in copy number downstream of PRPF31 gene on chromosome 19q13.4 between coordinates 59410000-59450000, in individuals homozygous for high (HH) and low (LL) expression of PRPF31 and a symptomatic and asymptomatic individual. This information will also be useful for formulating and testing potential future gene or gene-based therapies.

Type: Thesis (Doctoral)
Title: Investigating the molecular basis of partial penetrance with splicing factor gene, PRPF31, implicated in Retinitis Pigmentosa
Language: English
Additional information: Authorisation for digitisation not received
UCL classification: 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/16747
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