Chen Yabin, Jia Xiaoyun, Wang Panfeng, Xiao Xueshan, Li Shiqiang, Guo Xiangming, Zhang Qingjiong
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
Mol Vis. 2013;19:292-302. Epub 2013 Feb 6.
Dominant optic atrophy (DOA) is the most common form of autosomal inherited optic neuropathy, mainly caused by mutations in the optic atrophy 1 (OPA1) gene. The purpose of this study was to detect OPA1 gene mutations and associated phenotypes in Chinese patients with suspected hereditary optic neuropathy.
A cohort of 193 Chinese families with suspected hereditary optic neuropathy was collected, which had been excluded from the three common primary mitochondrial DNA mutations associated with Leber hereditary optic neuropathy in our prior screening. Sanger sequencing was used to analyze variants in the coding and adjacent regions of OPA1.
In this study, 11 heterozygous OPA1 mutations, among which eight were novel and three were known, were identified in 12 of the 193 families (6.2%) but in none of the 192 control individuals. These novel mutations consisted of two nonsense mutations (p.E707* and p.K797*), two missense mutations (p.T330S and p.V377I), two deletions (p.S64fs and p.L331fs), one small insertion (p.L17fs), and one splice site mutation (c.2614-2A>G). Of the 12 families, three had a family history of optic neuropathy while nine were sporadic cases. Analysis of the family members in the two sporadic cases demonstrated that one parent in each of the two families had the OPA1 mutation and mild phenotype of optic atrophy. A 4-year-old boy with severe ocular phenotype was found to be compound heterozygous for two OPA1 mutations, a p.S64fs frameshift deletion and a p.V377I missense mutation, possibly implying an additive effect.
This study implies that the frequency of DOA is much lower than that of Leber hereditary optic neuropathy in Chinese compared with other ethnic groups. Lack of awareness of the mild phenotype of DOA may contribute to the low frequency of OPA1-related DOA in Chinese. The phenotype associated with compound heterozygous OPA1 mutations may suggest a possible addictive effect.
显性遗传性视神经萎缩（DOA）是常染色体遗传性视神经病变的最常见形式，主要由视神经萎缩1（OPA1）基因突变引起。本研究旨在检测疑似遗传性视神经病变的中国患者的OPA1基因突变及相关表型。
收集了193个疑似遗传性视神经病变的中国家系队列，这些家系在我们之前的筛查中已被排除与Leber遗传性视神经病变相关的三种常见原发性线粒体DNA突变。采用桑格测序法分析OPA1编码区和相邻区域的变异。
在本研究中，193个家系中的12个（6.2%）鉴定出11个OPA1杂合突变，其中8个为新突变，3个为已知突变，而192名对照个体均未检出。这些新突变包括两个无义突变（p.E707和p.K797）、两个错义突变（p.T330S和p.V377I）、两个缺失突变（p.S64fs和p.L331fs）、一个小插入突变（p.L17fs）和一个剪接位点突变（c.2614-2A>G）。在这12个家系中，3个有家系性视神经病变病史，9个为散发病例。对两个散发病例的家庭成员分析表明，两个家系中各有一位家长携带OPA1突变且具有轻度视神经萎缩表型。一名患有严重眼部表型的4岁男孩被发现为两个OPA1突变的复合杂合子，即p.S64fs移码缺失突变和p.V377I错义突变，这可能意味着存在累加效应。
本研究提示，与其他种族相比，中国人群中DOA的发病率远低于Leber遗传性视神经病变。对DOA轻度表型认识不足可能是中国人群中OPA1相关DOA发病率较低的原因。与OPA1复合杂合突变相关的表型可能提示存在累加效应。
