The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.
The severity of retinal pathology in homozygous Crb1rd8/rd8 mice is dependent on additional genetic factors.
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纯合CRB1RD8/RD8小鼠中视网膜病理的严重程度取决于其他遗传因素。
DOI：
10.1093/hmg/ddu424
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Ali RR
中科院分区：
文献类型：
--
作者：
Luhmann UF;Carvalho LS;Holthaus SM;Cowing JA;Greenaway S;Chu CJ;Herrmann P;Smith AJ;Munro PM;Potter P;Bainbridge JW;Ali RR
了解视网膜变性的表型-基因型相关性是一个重大挑战。CRB 1突变导致一系列常染色体隐性视网膜营养不良，其表型可变，表明修饰因子的影响。为了建立与Crb 1 rd 8/rd 8突变相关的表型变异的遗传背景的贡献，我们比较了Crb 1 rd 8/rd 8/J近交系小鼠与C57 BL/6 JOlaHsd小鼠回交的两个Crb 1 rd 8/rd 8系的视网膜病理学。局部内镜眼底成像和扫描激光眼底镜眼底图像的所有三个Crb 1 rd 8/rd 8线显示了显着增加的数量下视网膜病变，是惊人的变化之间的线。光学相干断层扫描、半薄切片、超微结构形态学以及通过免疫组织化学和定量逆转录酶-聚合酶链反应对炎症和血管标记物的评估显示，病变与感光细胞死亡、Müller和小胶质细胞活化以及毛细血管扩张样血管重塑相关--这些特征在近交系中稳定，在第二系中可变，但在第三系Crb 1 rd 8/rd 8中几乎不存在，即使是在12个月大的时候这表明Crb 1 rd 8/rd 8突变是必要的，但不足以发展这些退行性特征。通过基因型-表型相关性的全基因组SNP分析，确定了15号染色体上的候选区域。这可能携带一种或多种遗传修饰剂，用于表现与Crb 1突变相关的视网膜病理学。这项研究还提供了对视网膜血管病变性质的深入了解，这些病变可能代表了CRB 1突变患者视网膜毛细血管扩张或Coats样血管病变形成的临床相关性，CRB 1突变被认为依赖于此类遗传修饰剂。
Understanding phenotype–genotype correlations in retinal degeneration is a major challenge. Mutations in CRB1 lead to a spectrum of autosomal recessive retinal dystrophies with variable phenotypes suggesting the influence of modifying factors. To establish the contribution of the genetic background to phenotypic variability associated with the Crb1rd8/rd8 mutation, we compared the retinal pathology of Crb1rd8/rd8/J inbred mice with that of two Crb1rd8/rd8 lines backcrossed with C57BL/6JOlaHsd mice. Topical endoscopic fundal imaging and scanning laser ophthalmoscopy fundus images of all three Crb1rd8/rd8 lines showed a significant increase in the number of inferior retinal lesions that was strikingly variable between the lines. Optical coherence tomography, semithin, ultrastructural morphology and assessment of inflammatory and vascular marker by immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction revealed that the lesions were associated with photoreceptor death, Müller and microglia activation and telangiectasia-like vascular remodelling—features that were stable in the inbred, variable in the second, but virtually absent in the third Crb1rd8/rd8 line, even at 12 months of age. This suggests that the Crb1rd8/rd8 mutation is necessary, but not sufficient for the development of these degenerative features. By whole-genome SNP analysis of the genotype–phenotype correlation, a candidate region on chromosome 15 was identified. This may carry one or more genetic modifiers for the manifestation of the retinal pathology associated with mutations in Crb1. This study also provides insight into the nature of the retinal vascular lesions that likely represent a clinical correlate for the formation of retinal telangiectasia or Coats-like vasculopathy in patients with CRB1 mutations that are thought to depend on such genetic modifiers.
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影响因子：
3.7
作者：
Luhmann UF;Lange CA;Robbie S;Munro PM;Cowing JA;Armer HE;Luong V;Carvalho LS;MacLaren RE;Fitzke FW;Bainbridge JW;Ali RR
通讯作者：
Ali RR
影响因子：
1.7
作者：
Eichler, W;Yafai, Y;Reichenbach, A
通讯作者：
Reichenbach, A
影响因子：
20.3
作者：
Fantin, Alessandro;Vieira, Joaquim M.;Ruhrberg, Christiana
通讯作者：
Ruhrberg, Christiana
影响因子：
--
作者：
Lotery, AJ;Jacobson, SG;Stone, EM
通讯作者：
Stone, EM
影响因子：
4.4
作者：
Jobling, Andrew I.;Vessey, Kirstan A.;Fletcher, Erica L.
通讯作者：
Fletcher, Erica L.