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T. Rio Frio, N. Civic, C. Rivolta; Genetic Elements Determining Penetrance of PRPF31 (RP11) Mutations. Invest. Ophthalmol. Vis. Sci. 2007;48(13):6004.
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© ARVO (1962-2015); The Authors (2016-present)
Penetrance of dominant PRPF31 mutations in heterozygote patients with dominant retinitis pigmentosa is linked to the expression of the remaining wild type allele. Indeed, affected carriers express lower amounts of the non-mutated PRPF31 mRNA allele than asymptomatic carriers, and therefore higher PRPF31 expression likely constitute a "protecting factor" from developing the disease. Previous studies have indicated that this protecting factor is likely to be present naturally in the general population. The aim of this project is to identify the genomic region(s) controlling PRPF31 expression and thus the penetrance of PRPF31 mutations, by using PRPF31 expression as phenotypic trait and performing genomewide linkage analysis.
CEPH cells are immortalized lymphoblastoid cell lines derived from large families sampled from the general, healthy population, which were also extensively genotyped. PRPF31 mRNA expression levels were measured in 155 CEPH cell lines (15 families) and in 7 lymphoblastoid cell lines from affected carriers of PRPF31 mutations, by quantitative RT-PCR. Due to the low inter individual variation of PRPF31 expression among CEPH cells, a very sensitive, accurate, robust and reproducible method was developed to precisely quantify PRPF31 mRNA expression level. Linkage analysis was performed using the MERLIN software.
Normalized to a CEPH PRPF31 medium expressor (expression of 1.0), PRPF31 expression in CEPH cells varied from 0.6 to 2.2 with an heritability among the families of 0.35 (p-value of 3.9*10-4). Preliminary linkage analyses indicated a number of genomic regions showing a LOD score of approximately 3 with significant p-values and thus possibly responsible for the high expression and the penetrance of PRPF31 mutations. To confirm the robustness of these LOD scores, a number of simulation studies are in progress. PRPF31 expression levels in affected patients are located outside the "normal" range, as defined by the CEPH set, since they score between 0.28 and 0.5.
Significant heritability of PRPF31 expression among CEPH families strongly supports the hypothesis that penetrance of PRPF31 mutation is due to a heritable genetic element. After validation of the linkage data, we will proceed to analyze the genetic regions where this element should lie, in hopes of identifying it. Furthermore, we also confirmed that patient cell lines with PRPF31 mutations produce a lower amount of PRPF31 mRNA than the general population, reinforcing the current hypothesis that the mechanism of PRPF31-associated retinitis pigmentosa is likely caused by haploinsufficiency.
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