未经证实:FAM161A的致病变异是以色列视网膜色素变性的最常见原因。两个创始人致病变异解释了绝大多数犹太血统的病例,1是无意义的变体(p。Arg523*).这项研究的目的是产生一个敲入(KI)小鼠模型,该模型具有相应的p.Arg512*致病变体并表征视网膜疾病的病程。
未经鉴定:小鼠动物模型的实验研究。
未经证实:共有106只Fam161a敲入小鼠和29只具有C57BL/6J背景的野生型小鼠参与了这项研究。
未经授权:纯合Fam161ap.Arg512*KI小鼠由CyagenBiosciences产生。视敏度(VA)使用视运动跟踪反应进行评估,视网膜功能通过视网膜电图(ERG)进行评估。使用OCT和眼底自发荧光成像在体内检查视网膜结构。通过组织学和免疫组织化学(IHC)分析评估视网膜形态。
未经评估:视觉和视网膜功能评估,临床影像学检查,定量组织学,和与野生型(WT)小鼠视网膜相比的KI的IHC研究。
UNASSIGNED:KI模型是通过替换3bp来生成的,导致p.Arg512*。纯合子KI小鼠,直到18个月大的VA和ERG反应逐渐丧失,在21个月时没有检测到的反应。OCT显示在21个月时外核层完全丧失。眼底自发荧光成像显示血管逐渐变窄,并形成斑片状的高自发荧光和低自发荧光斑点。组织学分析显示光感受器核逐渐丧失。免疫组织化学染色显示Fam161a主要在WT小鼠视网膜的光感受器纤毛和外丛状层(OPL)中表达,而微弱的表达主要在KI小鼠的纤毛和OPL中明显。
UNASSIGNED:Fam161a-p.Arg512*KI小鼠模型的特征是广泛的视网膜变性,进展相对缓慢。令人惊讶的是,与先前报道的敲除模型相比,疾病发作延迟且进展较慢.KI小鼠模型中常见的人类无效突变可能通过翻译通读诱导药物以及基因增强疗法和RNA编辑进行校正,并且可以用来测试这些治疗方法,作为可能在患者中应用的第一步。
UNASSIGNED:作者对本文讨论的任何材料都没有专有或商业利益。
UNASSIGNED: Pathogenic variants in FAM161A are the most common cause of retinitis pigmentosa in Israel. Two founder pathogenic variants explain the vast majority of cases of Jewish origin, 1 being a nonsense variant (p.Arg523∗). The aim of this study was to generate a knock-in (KI) mouse model harboring the corresponding p.Arg512∗ pathogenic variant and characterize the course of retinal disease.
UNASSIGNED: Experimental study of a mouse animal model.
UNASSIGNED: A total of 106 Fam161a knock-in mice and 29 wild-type mice with C57BL/6J background particiapted in this study.
UNASSIGNED: Homozygous Fam161a p.Arg512∗ KI mice were generated by Cyagen Biosciences. Visual acuity (VA) was evaluated using optomotor tracking response and retinal function was assessed by electroretinography (ERG). Retinal structure was examined in vivo using OCT and fundus autofluorescence imaging. Retinal morphometry was evaluated by histologic and immunohistochemical (IHC) analyses.
UNASSIGNED: Visual and retinal function assessments, clinical imaging examinations, quantitative histology, and IHC studies of KI as compared with wild-type (WT) mice retinas.
UNASSIGNED: The KI model was generated by replacing 3 bp, resulting in p.Arg512∗. Homozygous KI mice that had progressive loss of VA and ERG responses until the age of 18 months, with no detectable response at 21 months. OCT showed complete loss of the outer nuclear layer at 21 months. Fundus autofluorescence imaging revealed progressive narrowing of blood vessels and formation of patchy hyper-autofluorescent and hypo-autofluorescent spots. Histologic analysis showed progressive loss of photoreceptor nuclei. Immunohistochemistry staining showed Fam161a expression mainly in photoreceptors cilia and the outer plexiform layer (OPL) in WT mice retinas, whereas faint expression was evident mainly in the cilia and OPL of KI mice.
UNASSIGNED: The Fam161a - p.Arg512∗ KI mouse model is characterized by widespread retinal degeneration with relatively slow progression. Surprisingly, disease onset is delayed and progression is slower compared with the previously reported knock-out model. The common human null mutation in the KI mouse model is potentially amenable for correction by translational read-through-inducing drugs and by gene augmentation therapy and RNA editing, and can serve to test these treatments as a first step toward possible application in patients.
UNASSIGNED: The author(s) have no proprietary or commercial interest in any materials discussed in this article.