Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration
Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration
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DOI：
10.1086/510021
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发表时间：
2006-12-01
影响因子：
9.8
通讯作者：
Swaroop, Anand
中科院分区：
文献类型：
--
作者：
Friedman, James S.;Chang, Bo;Swaroop, Anand
rd 3小鼠是最早发现的早发性视网膜变性模型之一。使用位置候选方法，我们已经确定了一个新的基因，Rd 3，编码195个氨基酸的进化保守的蛋白质的C -> T取代。rd 3突变导致在残基106之后的预测终止密码子。在来源于原始收集的小鼠的四个rd 3系中观察到这种变化，但在检查的九个野生型小鼠品系中没有观察到这种变化。Rd 3优先在视网膜中表达，并且在出生后早期发育中表现出增加的表达。在瞬时转染的COS-1细胞中，RD 3融合蛋白显示出邻近早幼粒细胞白血病基因产物体的亚核定位。在COS-1细胞中可检测到截短的突变体RD 3蛋白，但似乎迅速降解。为了探索染色体1 q32处的人类RD 3基因与视网膜病变的潜在关联，我们对来自北美、印度和欧洲的881名先证者进行了突变筛查。除了几个变化的不确定的意义，我们确定了一个纯合性的RD 3外显子2供体剪接位点的不变G核苷酸的改变与Leber先天性黑蒙的两个兄弟姐妹。这种突变预计会导致RD 3蛋白的过早截短，与疾病分离，并且在121个种族匹配的对照个体中未检测到。我们认为视网膜病变相关的RD 3蛋白是亚核蛋白复合物的一部分，参与不同的过程，如转录和剪接。
The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C -> T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.