Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy
Mutations in TOPORS cause autosomal dominant retinitis pigmentosa with perivascular retinal pigment epithelium atrophy
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DOI：
10.1086/521953
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发表时间：
2007-11-01
影响因子：
9.8
通讯作者：
Bhattacharya, Shomi S.
中科院分区：
文献类型：
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作者：
Chakarova, Christina F.;Papaioannou, Myrto G.;Bhattacharya, Shomi S.
我们报告了常染色体显性色素性视网膜炎 (adRP) 患者中与染色体 9p21.1（RP31 位点）相关的拓扑异构酶 I 结合 RS 蛋白 (TOPORS) 基因的突变。位置克隆方法结合生物信息学，鉴定出 TOPORS（包含三个外显子，编码 1,045 个氨基酸的蛋白质）作为负责 adRP 的基因。已在两个受 adRP 影响的家庭（分别是一个法裔加拿大家庭和一个德国家庭）中发现了包括插入和缺失的突变。有趣的是，在疾病的早期阶段注意到了一种独特的表型，在视网膜的上拱廊和下拱廊周围发现了不寻常的血管周围视网膜色素上皮萎缩。 TOPORS 是一种含有 RING 结构域的 E3 泛素连接酶，定位于细胞核中与早幼粒细胞白血病体相关的斑点位点。 TOPORS 表达的普遍性和患者中突变蛋白的缺乏高度提示单倍体不足，而不是显性的负面效应，作为该疾病的分子机制，并使临床表型的拯救适合体细胞基因治疗。
We report mutations in the gene for topoisomerase I-binding RS protein (TOPORS) in patients with autosomal dominant retinitis pigmentosa (adRP) linked to chromosome 9p21.1 (locus RP31). A positional-cloning approach, together with the use of bioinformatics, identified TOPORS (comprising three exons and encoding a protein of 1,045 aa) as the gene responsible for adRP. Mutations that include an insertion and a deletion have been identified in two adRP-affected families-one French Canadian and one German family, respectively. Interestingly, a distinct phenotype is noted at the earlier stages of the disease, with an unusual perivascular cuff of retinal pigment epithelium atrophy, which was found surrounding the superior and inferior arcades in the retina. TOPORS is a RING domain-containing E3 ubiquitin ligase and localizes in the nucleus in speckled loci that are associated with promyelocytic leukemia bodies. The ubiquitous nature of TOPORS expression and a lack of mutant protein in patients are highly suggestive of haploinsufficiency, rather than a dominant negative effect, as the molecular mechanism of the disease and make rescue of the clinical phenotype amenable to somatic gene therapy.