Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa.
Adriana BuskinLili ZhuValeria ChichagovaBasudha BasuSina Mozaffari-JovinDavid DolanAlastair DroopJoseph CollinRevital BronsteinSudeep MehrotraMichael FarkasGerrit HilgenKathryn WhiteKuan-Ting PanAchim TreumannDean HallamKatarzyna BialasGit ChungCarla MelloughYuchun DingNatalio KrasnogorStefan PrzyborskiSimon ZwolinskiJumana Al-AamaSameer AlharthiYaobo XuGabrielle WhewayKatarzyna SzymanskaMartin McKibbinChris F InglehearnDavid J ElliottSusan LindsayRobin R AliDavid H W SteelLyle ArmstrongEvelyne SernagorHenning UrlaubEric PierceReinhard LührmannSushma-Nagaraja GrellscheidColin A JohnsonMajlinda LakoPublished in: Nature communications (2018)
Mutations in pre-mRNA processing factors (PRPFs) cause autosomal-dominant retinitis pigmentosa (RP), but it is unclear why mutations in ubiquitously expressed genes cause non-syndromic retinal disease. Here, we generate transcriptome profiles from RP11 (PRPF31-mutated) patient-derived retinal organoids and retinal pigment epithelium (RPE), as well as Prpf31+/- mouse tissues, which revealed that disrupted alternative splicing occurred for specific splicing programmes. Mis-splicing of genes encoding pre-mRNA splicing proteins was limited to patient-specific retinal cells and Prpf31+/- mouse retinae and RPE. Mis-splicing of genes implicated in ciliogenesis and cellular adhesion was associated with severe RPE defects that include disrupted apical - basal polarity, reduced trans-epithelial resistance and phagocytic capacity, and decreased cilia length and incidence. Disrupted cilia morphology also occurred in patient-derived photoreceptors, associated with progressive degeneration and cellular stress. In situ gene editing of a pathogenic mutation rescued protein expression and key cellular phenotypes in RPE and photoreceptors, providing proof of concept for future therapeutic strategies.
Keyphrases
- genome wide
- optical coherence tomography
- diabetic retinopathy
- genome wide identification
- bioinformatics analysis
- resting state
- gene expression
- multiple sclerosis
- dna methylation
- single cell
- optic nerve
- induced apoptosis
- genome wide analysis
- intellectual disability
- early onset
- binding protein
- staphylococcus aureus
- cell proliferation
- cell death
- transcription factor
- escherichia coli
- cell adhesion