A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.
A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.
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DOI：
10.1371/journal.pone.0137072
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Miyadera K
中科院分区：
文献类型：
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作者：
Kondo M;Das G;Imai R;Santana E;Nakashita T;Imawaka M;Ueda K;Ohtsuka H;Sakai K;Aihara T;Kato K;Sugimoto M;Ueno S;Nishizawa Y;Aguirre GD;Miyadera K
先天性静止性夜盲(CSNB)是一种非进行性、临床和遗传异质性的夜视障碍疾病。我们报告了一种自然发生的、静止的、常染色体隐性表型，患有白天视力正常但夜间视力缺失的比格犬。受影响的狗在临床检查中视网膜正常，但没有可检测到的视杆反应。他们在全场ERG中有“负性型”视杆细胞和视锥细胞混合反应。他们的明视长闪光ERG有正常的关闭反应，与严重降低的开启反应有关。该表型类似于人类完整的CSNB的Schubert-Bornschein形式。纯合性图谱排除了大多数已知的CSNB候选基因以及CACNA2D4和GNB3。根据开放阅读框架和内含子-外显子边界(Rho，NYX)的测序，排除了其余3个基因，这是由于CSNB(Rho)或X-染色体(NYX，CACNA1F)的不同形式所致。在光感受器及其突触终末、mGluR6级联和调节子表达的基因中，qRT-PCR检测到GNat1、CACNA2D4和NYX在携带者(n=2)和病变视网膜(n=2)中表达降低，而CACNA1F仅在病变视网膜中表达下调。视网膜形态显示正常的细胞层和结构，电子显微镜下显示正常的视杆球体和突触带。免疫组织化学(IHC)标记视杆细胞、视锥细胞及其突触前终末的免疫组织化学结果与正常无差异。所有的视网膜都没有显示出任何压力的迹象。选择mGluR6级联蛋白及其调节物进行免疫组化检测，发现PKCα弱标记受影响的杆状双极胞体，但强标记的轴突终末出现增厚和不规则。ON-双极细胞的树突状终末GO-α标记增强。PKCα和Goα都标记了更突出的双极树突，这些树突延伸到受影响但不是正常视网膜的OPL。有趣的是，RGS11在受影响的视网膜中没有标记。我们的结果表明，一个未知的基因参与了这个完全性CSNB的犬模型。
Congenital stationary night blindness (CSNB) is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had “negative-type” mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX), causal to a different form of CSNB (RHO) or X-chromosome (NYX, CACNA1F) location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2) and affected (n = 2) retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC) for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas. Interestingly, RGS11 showed no labeling in the affected retina. Our results indicate involvement of a yet unknown gene in this canine model of complete CSNB.