Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C > T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlatewith disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengthswas present inNPC RPEmonolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copyMSR1 repeat, but not with CNOT3 polymorphisms.
基金：
National Health and Medical Research Council of Australia [MRF1142962, GNT1116360, GNT1188694]; Ophthalmic Research Institute of Australia; Retina Australia
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类|3 区生物
小类|3 区遗传学
最新[2023]版：
大类|3 区生物学
小类|3 区遗传学
第一作者：
第一作者机构：[1]Univ Western Australia, Ctr Ophthalmol & Visual Sci, Nedlands, WA 6009, Australia[2]Lions Eye Inst, Ocular Tissue Engn Lab, Nedlands, WA 6009, Australia
通讯作者：
通讯机构：[1]Univ Western Australia, Ctr Ophthalmol & Visual Sci, Nedlands, WA 6009, Australia[*1]Univ Western Australia, Ctr Ophthalmol & Visual Sci, Nedlands, WA 6009, Australia[2]Lions Eye Inst, Ocular Tissue Engn Lab, Nedlands, WA 6009, Australia[*2]Lions Eye Inst, Ocular Tissue Engn Lab, Nedlands, WA 6009, Australia[3]Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Murdoch, WA 6150, Australia[*3]Murdoch Univ, Ctr Mol Med & Innovat Therapeut, Murdoch, WA 6150, Australia[4]Sir Charles Gairdner Hosp, Australian Inherited Retinal Dis Registry & DNA B, Dept ofMed Technol & Phys, Nedlands, WA 6009, Australia[*4]Sir Charles Gairdner Hosp, Australian Inherited Retinal Dis Registry & DNA B, Dept ofMed Technol & Phys, Nedlands, WA 6009, Australia[5]Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia[*5]Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Nedlands, WA 6009, Australia[6]Royal Perth Hosp, Dept Ophthalmol, Perth, WA 6000, Australia[*6]Royal Perth Hosp, Dept Ophthalmol, Perth, WA 6000, Australia[7]Perth Childrens Hosp, Dept Ophthalmol, Nedlands, WA 6009, Australia[*7]Perth Childrens Hosp, Dept Ophthalmol, Nedlands, WA 6009, Australia
推荐引用方式(GB/T 7714)：
McLenachan Samuel,Zhang Dan,Grainok Janya,et al.Determinants of Disease Penetrance in PRPF31-Associated Retinopathy[J].GENES.2021,12(10):1542.doi:10.3390/genes12101542.
APA：
McLenachan, Samuel,Zhang, Dan,Grainok, Janya,Zhang, Xiao,Huang, Zhiqin...&Chen, Fred K..(2021).Determinants of Disease Penetrance in PRPF31-Associated Retinopathy.GENES,12,(10)
MLA：
McLenachan, Samuel,et al."Determinants of Disease Penetrance in PRPF31-Associated Retinopathy".GENES 12..10(2021)
