Heterozygous deletions of noncoding parts of the PRPF31 gene cause retinitis pigmentosa via reduced gene expression

Heterozygous mutations in the gene; PRPF31; , encoding a pre-mRNA splicing factor, cause autosomal dominant retinitis pigmentosa (adRP) with reduced penetrance. At the molecular level, pathogenicity results from haploinsufficiency, as the largest majority of such mutations trigger nonsense-mediated mRNA decay or involve large deletions of coding exons. We investigated genetically two families with a history of adRP, one of whom showed incomplete penetrance.; All patients underwent thorough ophthalmological examination, including electroretinography (ERG) and Goldmann perimetry. Array-based comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) were used to map heterozygous deletions, while real-time PCR on genomic DNA and long-range PCR allowed resolving the mutations at the base-pair level.; PRPF31; transcripts were quantified with real-time PCR on patient-derived lymphoblastoid cell lines.; We identified two independent deletions affecting the promoter and the 5' untranslated region (UTR) of; PRPF31; but leaving its coding sequence completely unaltered. Analysis of; PRPF31; mRNA from lymphoblastoid cell lines from one of these families showed reduced levels of expression in patients versus controls, probably due to the heterozygous ablation of its promoter sequences.; In addition to reporting the identification of two novel noncoding deletions in; PRPF31; , this study provides strong additional evidence that mRNA-mediated haploinsufficiency is the primary cause of pathogenesis for; PRPF31; -linked adRP.