Purchase this article with an account.
SS Bhattacharya, L Safieh, E Vithana, M Papaioannou, AT Moore, AC Bird, DM Hunt; Identification of New Mutations in PRPF31, the Autosomal Dominant Retinitis Pigmentosa Gene on 19q13.4 . Invest. Ophthalmol. Vis. Sci. 2002;43(13):794.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Retinitis pigmentosa (RP) is clinically and genetically heterogeneous group of diseases. The adRP locus on 19q13.4 was first identified in our laboratory by linkage analysis in a large British family. Screening of all genes identified in the RP11 critical interval in the affected members of RP11 linked families led to the identification of mutations in a gene (PRPF31) that encodes a protein with homology to yeast pre-mRNA splicing factor Prp31p. Methods: We amplified coding exons from patient genomic DNA. PCR products were purified using Qiaquick columns (Qiagen). Denaturing High Performance Liquid Chromatography (DHPLC) and direct sequencing was used for mutation detection. Results: Based on the number of families linked to 19q this locus was thought to be the second most common locus after Rhodopsin. To date we have identified putative pathogenic mutations in four of our RP11 families and in four individuals in a cohort of 275 sporadic adRP cases from the UK. None of the mutations were present in 100 control subjects, thereby excluding the possibility that the identified mutations were polymorphisms. Here we report two deletions in two RP11 linked families. The AD2 family had a deletion of ∼60kb that removed the entire PRPF31 gene as well as two upstream genes. The second RP11 family (AD11) had a deletion of ∼100bp in the first exon which may affect the transcription of PRPF31. The four mutations identified in sporadic RP individuals include two missense mutations and two insertions. The two missense mutations were A194E and A211Q. The first duplication insertion resulted in a longer protein of 510 residues due to an in-frame insertion of 11 amino acid residues, while the other insertion gives rise to premature termination of the mRNA translation. Conclusion: The preponderance of protein truncation mutations in RP11 suggests that the usual pathophysiological basis of adRP at this locus is functional loss of one allele resulting in haploinsuffiency. Although the RP11 locus, based of number of linked families appeared to be a common cause of adRP, it was not reflected in the panel screen. This may attributable to PCR being unable to detect the majority of mutations present in PRPF31 such as large deletion or insertion mutations.
This PDF is available to Subscribers Only