Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.
Two novel CRX mutant proteins causing autosomal dominant Leber congenital amaurosis interact differently with NRL.
复制标题
DOI：
10.1002/humu.21268
复制
发表时间：
2010-06
期刊：
影响因子：
3.9
通讯作者：
Brooks, Brian P.
中科院分区：
文献类型：
--
作者：
Il, Lorenzo L. Nichols;Alur, Ramakrishna P.;Boobalan, Elangovan;Sergeev, Yuri V.;Caruso, Rafael C.;Stone, Edwin M.;Swaroop, Anand;Johnson, Mary A.;Brooks, Brian P.
关键词：
Leber先天性黑色素沉着症是一种先天性视网膜营养不良症，以婴儿期严重视力丧失和眼球震颤为特征。虽然大多数人通常以常染色体隐性遗传的方式遗传，但极少数带有锥体-杆状同源框基因CRX突变的个体患有显性疾病。CRX对光感受器的发育至关重要，并与亮氨酸拉链转录因子NRL协同作用。我们报告了两个新的CRX新突变导致的LCA患者的表型，c.G264T(p.K74N)和c.413delT(p.I138fs48)，它们分别将体外反式激活减少到对照的10%和30%。虽然c.413delT(p.I138fs48)突变体允许共表达的NRL在其正常的基线水平上独立反式激活，但c.G264T(p.K74N)突变体减少了共表达的NRL的反式激活，并降低了两种蛋白的稳定水平。虽然这两种突变蛋白主要定位于细胞核，但它们也都表现出不同的细胞质定位。这些观察表明，一些CRX介导的LCA可能是单倍体不足以外的效应所致，例如突变蛋白干扰了其他转录因子的功能。因此，这类患者不太可能从针对他们的疾病的简单的基因替代策略中受益。
Leber congenital amaurosis (LCA) is a congenital retinal dystrophy characterized by severe visual loss in infancy and nystagmus. Although most often inherited in an autosomal recessive fashion, rare individuals with mutations in the cone-rod homeobox gene, CRX, have dominant disease. CRX is critical for photoreceptor development and acts synergistically with the leucine-zipper transcription factor, NRL. We report on the phenotype of two individuals with LCA due to novel, de novo CRX mutations, c.G264T(p.K74N) and c.413delT(p.I138fs48), that reduce transactivation in vitro to 10% and 30% of control values, respectively. Whereas the c.413delT(p.I138fs48) mutant allows co-expressed NRL to transactivate independently at its normal, baseline level, the c.G264T(p.K74N) mutant reduces co-expressed NRL transactivation and reduces steady state levels of both proteins. Although both mutant proteins predominantly localize normally to the nucleus, they also both show variable cytoplasmic localization. These observations suggest that some CRX-mediated LCA may result from effects beyond haploinsufficiency, such as the mutant protein interefering with other transcription factors’ function. Such patients would therefore not likely benefit from a simple, gene-replacement strategy for their disease.
登录
查看更多内容
影响因子：
16.2
作者：
Chen, SM;Wang, QL;Zack, DJ
通讯作者：
Zack, DJ
影响因子：
30.8
作者：
Mears, AJ;Kondo, M;Swaroop, A
通讯作者：
Swaroop, A
影响因子：
5.6
作者：
LEE, C
通讯作者：
LEE, C
影响因子：
4.8
作者：
Kimura, A;Singh, D;Shinohara, T
通讯作者：
Shinohara, T
影响因子：
64.5
作者：
Furukawa, T;Morrow, EM;Cepko, CL
通讯作者：
Cepko, CL