Mehalow Adrienne K, Kameya Shuhei, Smith Richard S, Hawes Norman L, Denegre James M, Young James A, Bechtold Lesley, Haider Neena B, Tepass Ulrich, Heckenlively John R, Chang Bo, Naggert Jürgen K, Nishina Patsy M
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Hum Mol Genet. 2003 Sep 1;12(17):2179-89. doi: 10.1093/hmg/ddg232. Epub 2003 Jul 15.
Mutations within the CRB1 gene have been shown to cause human retinal diseases including retinitis pigmentosa and Leber congenital amaurosis. We have recently identified a mouse model, retinal degeneration 8 (rd8) with a single base deletion in the Crb1 gene. This mutation is predicted to cause a frame shift and premature stop codon which truncates the transmembrane and cytoplasmic domain of CRB1. Like in Drosophila crumbs (crb) mutants, staining for adherens junction proteins known to localize to the external limiting membrane, the equivalent of the zonula adherens in the mammalian retina, is discontinuous and fragmented. Shortened photoreceptor inner and outer segments are observed as early as 2 weeks after birth, suggesting a developmental defect in these structures rather than a degenerative process. Photoreceptor degeneration is observed only within regions of retinal spotting, which is seen predominantly in the inferior nasal quadrant of the eye, and is caused by retinal folds and pseudorosettes. Photoreceptor dysplasia and degeneration in Crb1 mutants strongly vary with genetic background, suggesting that the variability in phenotypes of human patients that carry mutations in CRB1 may be due to interactions with background modifiers in addition to allelic variations. The Crb1rd8 mouse model will facilitate the analysis of Crb1 function in the neural retina and the identification of interacting factors as candidate retinal disease genes.
已证实CRB1基因内的突变会导致人类视网膜疾病，包括色素性视网膜炎和莱伯先天性黑矇。我们最近鉴定出一种小鼠模型——视网膜变性8（rd8），其Crb1基因存在单个碱基缺失。预计该突变会导致移码和过早出现终止密码子，从而截断CRB1的跨膜和胞质结构域。与果蝇crumbs（crb）突变体一样，已知定位于外限制膜（相当于哺乳动物视网膜中的黏着小带）的黏着连接蛋白染色是不连续且碎片化的。早在出生后2周就观察到光感受器内段和外段缩短，这表明这些结构存在发育缺陷而非退行性过程。仅在视网膜斑点区域观察到光感受器变性，视网膜斑点主要见于眼的鼻下象限，由视网膜褶皱和假玫瑰花结引起。Crb1突变体中的光感受器发育异常和变性在不同遗传背景下差异很大，这表明携带CRB1突变的人类患者表型的变异性可能除了等位基因变异外，还归因于与背景修饰因子的相互作用。Crb1rd8小鼠模型将有助于分析Crb1在神经视网膜中的功能，并鉴定相互作用因子作为候选视网膜疾病基因。
