Neuillé Marion, El Shamieh Said, Orhan Elise, Michiels Christelle, Antonio Aline, Lancelot Marie-Elise, Condroyer Christel, Bujakowska Kinga, Poch Olivier, Sahel José-Alain, Audo Isabelle, Zeitz Christina
INSERM, U968, Paris, France; CNRS, UMR_7210, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France.
INSERM, U968, Paris, France; CNRS, UMR_7210, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France.
PLoS One. 2014 Mar 5;9(3):e90342. doi: 10.1371/journal.pone.0090342. eCollection 2014.
Mutations in LRIT3, coding for a Leucine-Rich Repeat, immunoglobulin-like and transmembrane domains 3 protein lead to autosomal recessive complete congenital stationary night blindness (cCSNB). The role of the corresponding protein in the ON-bipolar cell signaling cascade remains to be elucidated. Here we genetically and functionally characterize a commercially available Lrit3 knock-out mouse, a model to study the function and the pathogenic mechanism of LRIT3. We confirm that the insertion of a Bgeo/Puro cassette in the knock-out allele introduces a premature stop codon, which presumably codes for a non-functional protein. The mouse line does not harbor other mutations present in common laboratory mouse strains or in other known cCSNB genes. Lrit3 mutant mice exhibit a so-called no b-wave (nob) phenotype with lacking or severely reduced b-wave amplitudes in the scotopic and photopic electroretinogram (ERG), respectively. Optomotor tests reveal strongly decreased optomotor responses in scotopic conditions. No obvious fundus auto-fluorescence or histological retinal structure abnormalities are observed. However, spectral domain optical coherence tomography (SD-OCT) reveals thinned inner nuclear layer and part of the retina containing inner plexiform layer, ganglion cell layer and nerve fiber layer in these mice. To our knowledge, this is the first time that SD-OCT technology is used to characterize an animal model for CSNB. This phenotype is noted at 6 weeks and at 6 months. The stationary nob phenotype of mice lacking Lrit3, which we named nob6, confirms the findings previously reported in patients carrying LRIT3 mutations and is similar to other cCSNB mouse models. This novel mouse model will be useful for investigating the pathogenic mechanism(s) associated with LRIT3 mutations and clarifying the role of LRIT3 in the ON-bipolar cell signaling cascade.
富含亮氨酸重复序列、免疫球蛋白样和跨膜结构域3蛋白（LRIT3）的编码基因发生突变会导致常染色体隐性完全先天性静止性夜盲（cCSNB）。相应蛋白在ON双极细胞信号级联反应中的作用仍有待阐明。在此，我们对一种市售的Lrit3基因敲除小鼠进行了遗传学和功能特征分析，该小鼠模型用于研究LRIT3的功能和致病机制。我们证实，基因敲除等位基因中插入的Bgeo/Puro盒引入了一个过早的终止密码子，推测该密码子编码一种无功能的蛋白。该小鼠品系不存在常见实验室小鼠品系或其他已知cCSNB基因中存在的其他突变。Lrit3突变小鼠表现出所谓的无b波（nob）表型，在暗视和明视视网膜电图（ERG）中，b波振幅分别缺失或严重降低。视动试验显示在暗视条件下视动反应大幅降低。未观察到明显的眼底自发荧光或视网膜组织学结构异常。然而，光谱域光学相干断层扫描（SD-OCT）显示这些小鼠的内核层以及包含内网状层、神经节细胞层和神经纤维层的部分视网膜变薄。据我们所知，这是首次使用SD-OCT技术对CSNB动物模型进行表征。这种表型在6周和6个月时均有记录。我们将缺乏Lrit3的小鼠的静止nob表型命名为nob6，这证实了先前在携带LRIT3突变的患者中报道的结果，并且与其他cCSNB小鼠模型相似。这种新型小鼠模型将有助于研究与LRIT3突变相关的致病机制，并阐明LRIT3在ON双极细胞信号级联反应中的作用。
