Compound Heterozygosity of Two Novel Truncation Mutations in RP1 Causing Autosomal Recessive Retinitis Pigmentosa
Compound Heterozygosity of Two Novel Truncation Mutations in RP1 Causing Autosomal Recessive Retinitis Pigmentosa
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DOI：
10.1167/iovs.09-4437
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发表时间：
2010-04-01
影响因子：
4.4
通讯作者：
Pang, Chi Pui
中科院分区：
文献类型：
--
作者：
Chen, Li Jia;Lai, Timothy Y. Y.;Pang, Chi Pui
目的。目的探讨常染色体隐性视网膜色素变性（ARRP）中国家系RP1基因两个新移码突变的表型效应。通过直接测序筛选ARRP先证家族成员的RP1、RHO、NR2E3和NRL突变。对225名对照受试者检测到的RP1突变进行基因分型。由于一名在2号外显子RP1缺失突变的家族成员被发现患有年龄相关性黄斑变性（AMD），而不是RP，我们在120例渗出性AMD患者中筛选了RP1的2和3号外显子。我们还研究了HTRA1和CFH基因中与amd相关的主要snp。在RP1中发现了两个新的移码突变，c.5 6delGT和c. 4941_4942insT。在225名对照受试者中没有出现。无义突变为复合杂合的家庭成员有早发性和严重的RP，而只有一个突变的家庭成员没有RP。在家系中未发现RHO、NR2E3和NRL突变。受试者1:2名AMD患者同时携带HTRA1 rs11200638和CFH rs800292两种高危基因型。在120例AMD患者中未发现RP1外显子2和3突变。该报告首次将ARRP与RP1的复合杂合无义突变联系起来。无义介导的mRNA衰变（NMD）敏感突变c.5 6delGT的鉴定提供了进一步的遗传学证据，证明RP1的单倍不足不是RP的原因。作者提出了RP1基因的四类截断突变，它们对RP的病因有不同的影响。（中国眼科杂志，2010;51:2236-2242）DOI:10.1167/iovs.09-4437
PURPOSE. To evaluate the phenotypic effects of two novel frameshift mutations in the RP1 gene in a Chinese pedigree of autosomal recessive retinitis pigmentosa (ARRP).METHODS. Family members of a proband with ARRP were screened for RP1, RHO, NR2E3, and NRL mutations by direct sequencing. Detected RP1 mutations were genotyped in 225 control subjects. Since one family member with the RP1 deletion mutation in exon 2 was found to have age-related macular degeneration (AMD) but not RP, exons 2 and 3 of RP1 were screened in 120 patients with exudative AMD. Major AMD-associated SNPs in the HTRA1 and CFH genes were also investigated.RESULTS. Two novel frameshift mutations in RP1, c.5 6delGT and c. 4941_4942insT, were identified in the pedigree. They were absent in 225 control subjects. Family members who were compound heterozygous for the nonsense mutations had early-onset and severe RP, whereas those with only one mutation did not have RP. No mutations in RHO, NR2E3, and NRL were identified in the pedigree. Subject I: 2 with AMD carried both at-risk genotypes at HTRA1 rs11200638 and CFH rs800292. No mutation in RP1 exons 2 and 3 was identified in 120 AMD patients.CONCLUSIONS. This report is the first to associate ARRP with compound heterozygous nonsense mutations in RP1. Identification of the nonsense-mediated mRNA decay (NMD)-sensitive mutation c.5 6delGT provided further genetic evidence that haploinsufficiency of RP1 is not responsible for RP. The authors propose four classes of truncation mutations in the RP1 gene with different effects on the etiology of RP. (Invest Ophthalmol Vis Sci. 2010;51:2236-2242) DOI:10.1167/iovs.09-4437