携带m．14484T〉C异质性突变的Leber遗传性视神经病变一家系的临床及遗传学特征  

A study of clinical and genetic characteristics of a Leber hereditary optic neuropathy family with the heteroplasmic m. 14484T〉C mutation

作　　者：孙颖[1] 雷珂[2] 徐则林 耿燕 Sun Ying;Lei Ke;Xu Zelin;C-eng Yan(Department of Ophthalmology,the Affiliated Central Hospital of Qingdao University,Qingdao 266042,Chin)

机构地区：[1]青岛大学附属中心医院眼科,266042 [2]青岛大学附属医院儿科研究所

出　　处：《中华眼科杂志》2018年第7期526-534,共9页Chinese Journal of Ophthalmology

摘　　要：目的研究携带m.14484T〉C异质性突变的Leber遗传性视神经病变（LHON）家系的临床及遗传学特征。方法横断面研究。研究对象为2015年3月在青岛大学附属中心医院眼科就诊的1例基因检测为m.14484T〉C异质性突变的31岁男性LHON患者（先证者）及其四代同堂家系中的其他36名母系成员[男性12名，女性24名，中位年龄27岁（2～81岁）]。对家系成员进行病史采集及视力、眼压、眼底、色觉、视野、视觉诱发电位（VEP）和相干光层析成像术（OCT）等眼科常规检查；其中33名家系成员抽取静脉血进行线粒体DNA（mtDNA）14484位点的Sanger测序，采用QSVanalyzer软件计算14484位点突变的异质性比例。先证者进行全线粒体基因组分析，与剑桥参考序列进行比对。VEP、OCT及突变的异质性比例两组间比较采用t检验，多组间比较采用单因素方差分析。结果33名母系成员中发现m.14484T〉C突变的LHON患者4例、突变携带者28名和无14484位点突变者1名，患病外显率为12.5%（4/32）。除4例患者眼科检查明显异常外，5名携带者也出现眼电生理和视功能异常。家系中患者和基因突变携带者的VEP结果相比，患者P100振幅低[（5.6±2.6）μV与（15.6±9.6）μV比较，t=2.880，P=0.006]；OCT结果相比，患者视网膜神经纤维层（RNFL）平均厚度薄[（71±17）μm与（99±11）μm比较，t=5.969，P〈0.001]，内子区黄斑区视网膜厚度在各象限均变薄，外子区黄斑区视网膜厚度仅在鼻侧象限明显变薄[（260±16）μm与（291±12）μm比较，t=5.593，P〈0.001]。LHON患者的基因突变异质性比例高达80%±3%，未患病的家系成员的异质性比例平均为27%±18%，差异有统计学意义（t=-8.395，P〈0.001）。男女成员间突变异质性比例差异无统计学意义（48%±34%与35%±28%比较，t=-1.147，P=0.258）。家系中的第Ⅱ、Ⅲ、Ⅳ代成员突变异质性比例分别为29%±14%、36ObjectiveTo study clinical and genetic characteristics of a Leber hereditary optic neuropathy （LHON） family with the heteroplasmic m.14484T〉C mutation.MethodsA cross-sectional study. The objects of the study included a 31-year-old male LHON patient with the heteroplasmic m.14484T〉C mutation （the proband） who visited Department of Ophthalmology in the Affiliated Central Hospital of Qingdao University in March 2015 and other 36 matrilineal relatives in a four-generation family （12 males and 24 females aged 2-81 years, median 27 years）. The visual acuity, intraocular pressure, fundus, color vision, visual field, visual evoked potential and optical coherence tomography were evaluated in maternal members. The mitochondrial DNA （mtDNA） sequence of fragments including m.14484 loci was detected by Sanger sequencing in 33 members. The sequencing peaks were analyzed by QSVanalyzer software to get the heteroplasmy levels of m.14484T〉C mutation. The mtDNA of the proband was amplified by PCR and sequenced. Assembled sequence of mtDNA was compared with the updated consensus Cambridge sequence. The differences in visual evoked potential, optical coherence tomography and heteroplasmy levels were compared between two groups by the t-test, and among multiple groups by the single factor variance analysis. ResultsAmong the 33 maternal members of the family, 4 patients, 28 carriers and 1 person without a mutation were confirmed. The penetrance was 12.5% （4/32） . In addition to 4 patients with obvious abnormality on the ophthalmic examination, 5 carriers also appeared anomaly on the electrophysiological and visual function examinations. Compared to carriers, the amplitude of P100 was obviously decreased in the LHON patients[ （5.6±2.6） μV vs. （15.6±9.6） μV, t=2.880, P=0.006]. Significantly reduced values were seen in the average retinal nerve fiber layer thickness[ （71±17） μm vs. （99±11） μm, t=5.969, P〈 0.001], in each side of the sub-area macular thickness, and in the nasal side of

关 键 词：视神经萎缩 遗传性 LEBER 系谱 DNA 线粒体 遗传异质性 

分 类 号：R774.6[医药卫生—眼科]