Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family.
Mutations in NR2E3 can cause dominant or recessive retinal degenerations in the same family.
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DOI：
10.1002/humu.20858
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发表时间：
2009-03
期刊：
影响因子：
3.9
通讯作者：
Schorderet, Daniel F.
中科院分区：
文献类型：
--
作者：
Escher, Pascal;Gouras, Peter;Roduit, Raphael;Tiab, Leila;Bolay, Sylvain;Delarive, Tania;Chen, Shiming;Tsai, Chih-Cheng;Hayashi, Masanori;Zernant, Jana;Merriam, Joanna E.;Mermod, Nicolas;Allikmets, Rando;Munier, Francis L.;Schorderet, Daniel F.
关键词：
NR 2 E3（PNR）是一种在光感受器中特异表达的核受体，抑制视锥细胞特异性基因并激活几个视杆细胞特异性基因。在人类中，NR 2 E3的突变与Recombinant遗传性增强型短波长敏感（S-）视锥细胞综合征（ESCS）相关，最近与常染色体显性视网膜色素变性（adRP）相关。在目前的工作中，我们描述了另外两个受adRP影响的家族，它们在NR 2 E3基因中携带杂合c.166G>A（p.G56R）突变。功能分析确定p.G56R突变蛋白的显性负活性是adRP的分子机制。有趣的是，在一个家系中，ESCS最常见的致病变异体（p.R311Q）与adRP连锁的p.G56R突变共分离，并且复合杂合子表现出ESCS样表型，在2例病例中的1例中，这种表型比仅携带p.G56R突变的患者明显“温和”。辅阻遏物atrophin-1（齿状红核-苍白球路易氏体萎缩DRPLA基因产物）和atrophin-2（RERE重复蛋白）对视锥细胞特异性基因的抑制减弱似乎是介导p.R311Q突变有益作用的分子机制。最后，p.R311Q的功能优势的p.G56R突变进行了讨论。
NR2E3 (PNR), a nuclear receptor specifically expressed in photoreceptors, represses cone-specific genes and activates several rod-specific genes. In humans, mutations in NR2E3 have been associated with the recessively inherited enhanced short wavelength sensitive (S-) cone syndrome (ESCS) and, recently, with autosomal dominant retinitis pigmentosa (adRP). In the present work, we describe two additional families affected by adRP that carry a heterozygous c.166G>A (p.G56R) mutation in the NR2E3 gene. Functional analysis determined dominant negative activity of the p.G56R mutant protein as the molecular mechanism of adRP. Interestingly, in one pedigree, the most common causal variant for ESCS (p.R311Q) co-segregated with the adRP-linked p.G56R mutation, and, the compound heterozygotes exhibited an ESCS-like phenotype, which in one of the 2 cases was strikingly “milder” than the patients carrying the p.G56R mutation alone. Impaired repression of cone-specific genes by the corepressors atrophin-1 (dentatorubral-pallidoluysian atrophy DRPLA gene product) and atrophin-2 (RERE repeat protein) appeared to be a molecular mechanism mediating the beneficial effect of the p.R311Q mutation. Finally, the functional dominance of the p.R311Q to the p.G56R mutation is discussed.
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