Disease relevance of PRPF31

• PURPOSE: To describe the clinical and genetic characteristics of three Japanese families with autosomal dominant retinitis pigmentosa (ADRP) associated with mutations in the PRPF31 gene [1].
• To begin to understand mechanisms by which defects in this general splicing factor cause retinal degeneration, we examined the relationship between PRPF31 and pre-mRNA splicing of photoreceptor-specific genes [2].

High impact information on PRPF31

• A positional cloning approach supported by bioinformatics identified PRPF31 comprising 14 exons and encoding a protein of 499 amino acids [3].
• The results support the hypothesis that wild-type alleles at the RP11 locus or at a closely linked locus inherited from the noncarrier parents are a major factor influencing the penetrance of pathogenic alleles at this locus [4].
• In all three families the disease gene appears to be linked to chromosome 19q13.4, the region containing the RP11 locus, as defined by previously reported linkage studies based on five other reduced-penetrance families [4].
• We also compared the disease status of RP11 carriers with the segregation of microsatellite alleles within 19q13.4 from the noncarrier parents in the newly reported and the previously reported families [4].
• The recent identification of mutations in human splicing factors, PRPF31 and PRPC8, led us to screen HPRP3 as a candidate in three chromosome 1q-linked families [5].

Biological context of PRPF31

• The existence of asymptomatic carriers of the nonsense mutation in the PRPF31 gene suggests incomplete penetrance for these mutations in the families [6].
• This study was intended to identify mutations in PRPF3, PRPF8, and PRPF31 in 150 Spanish families affected by adRP, to measure the contribution of mutations in these genes to adRP in that population, and to correlate RP phenotype expression with mutations in pre-mRNA splicing-factor genes [6].
• To investigate the possibility of a large deletion, microsatellite markers near PRPF31 gene were analyzed by non-denaturing PAGE [7].
• A large deletion was however suspected due to lack of heterozygosity for nearly all PRPF31 intragenic single nucleotide polymorphysm (SNPs) [7].
• CONCLUSIONS: In this first report of molecular genetic analysis of retinitis pigmentosa in Romani families, we describe a novel PRPF31 mutation and present the first case of a homozygous mutation in the RPGR gene in a female individual [8].

Anatomical context of PRPF31

• The use of cell lines was validated by the observation that cell transformation did not alter PRPF31 expression in the cell lines compared with nucleated blood cells and donor retinas [9].
• This primary retinal culture assay provides an in vitro model to study photoreceptor cell death caused by PRPF31 mutations [2].
• It seems likely that a protein homologous to mammalian SMP-69 is involved in the mechanisms controlling excitability and long-term specific plasticity of the synaptic inputs to neurons LP11 and RP11 from chemoreceptors on the snail's head [10].

Associations of PRPF31 with chemical compounds

• Within the region, a single nucleotide change (G>A) at position -1 of Intron 5 of PRPF31 was found [11].
• Here we analyzed RNA structural requirements for association of hPrp31 with U4 snRNP in vitro by hydroxyl radical footprinting. hPrp31 induced protection of the terminal penta-loop, as well as of stems I and II flanking the kink-turn [12].
• Experiments on semi-intact preparations from common snails were used to study the characteristics of the actions of MK-801, an antagonist of NMDA glutamate receptors, on the plasticity of various sensory inputs to defensive behavior command neurons LP11 and RP11 during acquisition of nociceptive sensitization [13].
• The neuronal effects of antibody SMP-69 were similar to changes in the activity of cells LP11 and RP11 induced by serotonin and cAMP, and to changes seen when snails acquired nociceptive sensitization [10].
• Studies of defensive behavior command neurons LP11 and RP11 in semi-intact common snail preparations addressed the effects of the protein kinase C antagonist polymyxin B on the effect of nociceptive sensitization [14].

Other interactions of PRPF31

• CONCLUSIONS: Nine mutations, six of which are novel, in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31, causing adRP have been identified in the Spanish population [6].
• Three patients were heterozygous carriers of different nonsense mutations in exon 8 of the PRPF31, gene and one Thr494Met mutation was found in exon 11 of the PRPF3 gene [6].
• This study investigates the functional consequences of two mutations, A194E and A216P, in the splicing factor gene PRPF31 linked to autosomal dominant retinitis pigmentosa (RP11) [15].
• We investigated (CAG)n expansions as a cause of disease in a panel of eight autosomal dominant retinitis pigmentosa (ADRP) pedigrees, including families known to map to the RP9, RP11, and RP13 loci, using the technique known as "repeat expansion detection" (RED) [16].
• RNA Structural Requirements for the Association of the Spliceosomal hPrp31 Protein with the U4 and U4atac Small Nuclear Ribonucleoproteins [12].

Analytical, diagnostic and therapeutic context of PRPF31

• However, western analysis and immunofluorescence microscopy of mammalian cells transfected with PRPF31 revealed that both mutations substantially hinder translocation of the protein into the nucleus [15].
• The PRPF31 protein levels from symptomatic and asymptomatic individuals were also assayed by Western blot analysis using an antibody specific to the wild-type PRPF31 protein [9].
• Real-time quantitative RT-PCR was performed on RNA from lymphoblastoid cell lines derived from a large adRP family (RP856/AD5) that segregates an 11bp deletion in exon 11 of PRPF31 [9].
• Gene expression levels were measured by Affymetrix and CodeLink microarrays and, for RP11 transcripts, also by real-time PCR [17].

References