A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype
A Novel Nonsense Mutation in CEP290 Induces Exon Skipping and Leads to a Relatively Mild Retinal Phenotype
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DOI：
10.1167/iovs.09-5074
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发表时间：
2010-07-01
影响因子：
4.4
通讯作者：
den Hollander, Anneke I.
中科院分区：
文献类型：
--
作者：
Littink, Karin W.;Pott, Jan-Willem R.;den Hollander, Anneke I.
目的.目的：探讨一个视网膜表型变异家系的遗传缺陷。先证者被诊断为Leber先天性黑蒙（LCA），而她的两个堂兄弟患有早发性严重视网膜营养不良（EOSRD），具有有用的视力。一个远房家庭成员有视网膜色素变性（RP）。用250 K全基因组SNP微阵列对受影响的家庭成员的DNA样本进行基因分型。遗传缺陷通过连锁分析和纯合性定位，候选基因通过测序分析。患者接受了全面的眼科检查。在先证者和她的两个堂兄弟中发现了CEP 290的复合杂合突变：常见的c.2991 + 1655 A>G创始者突变和外显子7的新无义突变（c.451C>T，p.Arg151X）。先证者有眼球震颤、远视、平坦的视网膜电图（ERG）和出生后视力下降（20/250）。这两个堂兄弟在2岁时有最小的暗视ERG反应。在其中一名患者中，视力在5岁时达到20/32的水平，这对于CEP 290突变患者来说很高。在受影响的个人CEP 290 mRNA的分析显示改变剪接形式，其中外显子7或外显子7和8被跳过。在两种突变体cDNA产物中，开放阅读框未被破坏。此外，RP影响的远房家族成员的纯合性定位和突变分析显示MERTK纯合性突变，但没有CEP 290突变。这种MERTK突变在最严重受累（LCA）的患者中异源存在，但在两种较轻度受累的患者中不存在。CEP 290中一种新的无义突变导致无义相关的剪接改变。剩余的开放阅读框架是完整的，这可以解释在两个受影响的堂兄弟中观察到的不太严重的表型。MERTK中的额外杂合突变可能阐明先证者中更严重的表型。这项研究扩展了轻度CEP 290相关疾病的表型谱。（Invest Ophthalmol维斯科学。2010;51：3646-3652）DOI：10.1167/iovs.095074
PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP).METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination.RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991 + 1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins.CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end. (Invest Ophthalmol Vis Sci. 2010;51:3646-3652) DOI: 10.1167/iovs.095074