# The Pathogenesis of RNA Splicing Factor Associated Retinal Degeneration > **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2021 · $638,301 ## Abstract Project Summary/Abstract The broad, long-term objectives of the proposed research are to improve understanding of the pathogenesis of inherited retinal degeneration (IRD) due to mutations in genes that encode RNA splicing factors so that therapies can be developed for these blinding disorders. Mutations in 6 genes that encode components of the spliceosome, the ribonucleoprotein (RNP) complex that catalyses pre-mRNA splicing, have been identified to cause dominant IRD, including Pre-RNA Processing Factor 3 (PRPF3), PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200. Together, mutations in these 6 genes are the second most common cause of dominant IRD. Despite being relatively common, the mechanism(s) by which mutations in genes that encode components of the spliceosome and that are utilized in mRNA splicing ubiquitously lead to retina specific disease remain to be defined. Since all 6 dominant RNA splicing factor IRD disease genes encode proteins that are components of the U4/U6.U5 tri-snRNP (small nuclear RNP) subunit of the spliceosome, it is hypothesized that altered RNA splicing underlides the retinal degeneration in the RNA splicing factor forms of IRD. There is also good evidence that mutations in PRPF genes cause cell autonomous defects in RPE function, providing a model system for studies of disease pathogenesis and potential treatments. In the past funding period transcriptome analyses of tissues from PRPF31 mutant mice and human induced pluripotent stem cell (hiPSC) derived RPE cells were performed. Analyses of the data from the Prpf31 mutant mice indicate that the majority of differentially expressed (DE) genes in the RPE are targets of the AP-1 transcription factor complex. Further, alternative splicing (AS) of 11 genes that encode regulators of AP-1 activity was detected. These preliminary data provide a strong starting point for the proposed research, which is directed towards defining the causal chain of molecular events that lead from mutations in RNA splicing factors to retinal degeneration, and using this information to inform development of therapies for RNA splicing factor associated IRD. In Aim 1 the hypothesis that altered mRNA splicing of AP-1 regulators leads to down-regulation of AP-1 subunits in RPE cells will be tested by expressing the altered transcripts of the AP-1 regulators in RPE cells in culture and in vivo. The goal of Aim 2 is to test the hypothesis that altered mRNA splicing of genes associated with AP-1 complex activity also underlies RPE dysfunction due to mutations in human RNA splicing factor genes. This will be accomplished by performing transcriptome analyses of PRPF mutant hiPSC-derived RPE cells. In Aim 3 high content screening methods and CRISPR/Cas9 - based genome perturbation screens will be used to identify genes who altered expression is responsible for RPE dysfunction in PRPF-associated disease. Finally, the hypothesis that information derived from these studies has the potential to be used therapeutically... ## Key facts - **NIH application ID:** 10233432 - **Project number:** 2R01EY020902-10A1 - **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY - **Principal Investigator:** Eric A Pierce - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $638,301 - **Award type:** 2 - **Project period:** 2011-04-01 → 2025-03-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10233432 ## Citation > US National Institutes of Health, RePORTER application 10233432, The Pathogenesis of RNA Splicing Factor Associated Retinal Degeneration (2R01EY020902-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10233432. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*