Leber遗传性视神经病变的遗传学进展

1871年德国眼科医生Theodor Leber首次描述了一种遗传性眼病，主要表现为双眼急性或亚急性中心视力下降。多累及青年男性，随后便将此病命名为Leber遗传性视神经病变（Leber hereditary optic neuropathy，LHON）。现已证实该病为母系遗传性疾病，其主要病因是线粒体DNA（mitochondrial DNA，mtDNA）某些位点发生突变，是一种最为常见的线粒体遗传病。尽管现在对此病已进行了深入研究。但有很多方面尚需进一步讨论，例如：有关LHON突变基因位点的研究、LHON的不完全外显性、LHON的遗传种族差异性以及突变位点与临床表现和预后的关系等，本文就这几方面进行综述。     

Leber遗传性视神经病三个家系患者线粒体DNA突变位点的研究

目的对Leber遗传性视神经病（Leber’s hereditary optic neuropathy，LHON）家系的原发突变位点11778与继发突变位点9804、13708、13730、15257进行突变分析，探讨两者之间相关性及对LHON的影响。方法应用聚合酶链反应一单链构象多态性和DNA测序对3个LHON家系37位母系成员和47名正常人的线粒体DNA（mitochondrial DNA，mtDNA）进行检测。结果16例患者及其母系亲属均存在11778位点突变，未发现9804、13708、13730、15257位点突变，但DNA测序发现13759、13928、13942、15301、15326、15323这6个新突变位点。结论3个家系都存在mtDNA11778位点突变，在13759位点患者突变率远高于正常人，差异有统计学意义（P〈0．001），表明13759是LHON新的继发突变位点。     

线粒体DNA继发突变对Leber遗传性视神经病变的影响

Leber遗传性视神经病变(Leber hereditary optic neuropathy,LHON)是一种多发于青壮年的母系遗传性疾病,可导致双眼严重的急性无痛性、且一般是永久性的双侧中心视野缺失。三个线粒体DNA（mitochondrial DNA,mtDNA）原发突变ND4 G11778A、ND1 G3460A和ND6 T14484C是其致病的主要因素,但家族间及家族内不同成员之间的表型差异表明存在其它的修饰因子,包括核及线粒体遗传修饰因子,环境因素。本综述主要阐述mtDNA继发突变对LHON表型表达的影响。     

Leber遗传性视神经病变的研究进展

Leber遗传性视神经病变(Leber's hereditary optic neuropathy,LHON)是一种主要累及青壮年男性,导致视神经退行性变的母系遗传病.线粒体DNA(mitochondrial DNA,mtDNA)突变为LHON发病的主要分子基础.LHON不完全外显和男性好发的特征表明,其他因素(如mtDNA单体型、核修饰基因和/或环境因素等)在LHON发病中起着重要作用.     

Leber＇s遗传性视神经病线粒体DNA突变二例的检测

目的检测两例Leber＇s遗传性视神经病的突变位点.方法常规酚-氯仿法提取2名LHON患者基因组DNA,PCR扩增后对mtDNA11778进行检测.结果mtDNA11778位点处存在G→A突变.     

线粒体DNA11778突变所致Leber遗传性视神经病变外显率分析

目的 分析携带线粒体DNA（mitochondrialDNA,mtDNA)11778突变者视神经病变的外显率。方法 对经基因诊断确定为mtDNA11778突变的Leber遗传性视神经病变（Leber hereditary optic neuropathy,LHON)家系进行分析。确定mtDNA11778突变携带者及患者。结果 16个家系中mtDNA11778突变携带者130人,其中男65人,女65人,130人突变携带者中43人患病,外显率33.1%。男性患者34人,男性外显率52.3%,女性患者9人,女性外显率13.8%,男女患病比率3.8:1,患者中男性占79%。结论 携带纯合性mtDNA11778位点突变的中国人,LHON外显率近1/3。     

线粒体DNA继发突变对Leber遗传性视神经病变的影响

Leber遗传性视神经病变是一种多发于青壮年的母系遗传性疾病,可导致双眼严重的急性无痛性、且一般是永久性的双侧中心视野缺失.3个线粒体DNA(mitochondrial DNA,mtDNA)原发突变ND4 G11778A、ND1 G3460A和N06 T14484C是其致病的主要因素,但家族问及家族内不同成员之间的表型差异表明存在其他的修饰因子,包括核及线粒体遗传修饰因子、环境因素.本综述主要阐述mtDNA继发突变对LHON表型表达的影响.     

线粒体DNA继发突变对Leber遗传性视神经病变的影响

Leber遗传性视神经病变是一种多发于青壮年的母系遗传性疾病,可导致双眼严重的急性无痛性、且一般是永久性的双侧中心视野缺失.3个线粒体DNA(mitochondrial DNA,mtDNA)原发突变ND4 G11778A、ND1 G3460A和N06 T14484C是其致病的主要因素,但家族问及家族内不同成员之间的表型差异表明存在其他的修饰因子,包括核及线粒体遗传修饰因子、环境因素.本综述主要阐述mtDNA继发突变对LHON表型表达的影响.     

线粒体DNA继发突变对Leber遗传性视神经病变的影响

Leber遗传性视神经病变是一种多发于青壮年的母系遗传性疾病,可导致双眼严重的急性无痛性、且一般是永久性的双侧中心视野缺失.3个线粒体DNA(mitochondrial DNA,mtDNA)原发突变ND4 G11778A、ND1 G3460A和N06 T14484C是其致病的主要因素,但家族问及家族内不同成员之间的表型差异表明存在其他的修饰因子,包括核及线粒体遗传修饰因子、环境因素.本综述主要阐述mtDNA继发突变对LHON表型表达的影响.     

线粒体DNA继发突变对Leber遗传性视神经病变的影响

Leber遗传性视神经病变是一种多发于青壮年的母系遗传性疾病,可导致双眼严重的急性无痛性、且一般是永久性的双侧中心视野缺失.3个线粒体DNA(mitochondrial DNA,mtDNA)原发突变ND4 G11778A、ND1 G3460A和N06 T14484C是其致病的主要因素,但家族问及家族内不同成员之间的表型差异表明存在其他的修饰因子,包括核及线粒体遗传修饰因子、环境因素.本综述主要阐述mtDNA继发突变对LHON表型表达的影响.     

Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations

The mitochondrial DNAs (mtDNA) from 17 Caucasian 11778-positive and 30 Caucasian 11778-negative Leber's hereditary optic neuropathy (LHON) patients were PCR-amplified and subjected to high resolution restriction endonuclease analysis. Concurrently, all patient mtDNAs were screened for the common primary LHON mtDNA mutations at nucleotide pairs (nps) 3460, 11778, and 14484, the ambiguous intermediate-risk LHON mtDNA mutations at nps 5244 and 15257, and the secondary LHON mtDNA mutations at nps 3394, 4216, 4917, 7444, 13708, and 15812. Phylogenetic analysis was performed using mtDNA haplotype data from the 47 LHON patients and 175 non-LHON Caucasian controls. The superimposition of the LHON mutation screening results upon the Caucasian mtDNA phylogeny revealed (1) 35 different LHON haplotypes, (2) that all three common primary mutations have occurred multiple times in Caucasians, (3) that while recurrent mutation is common for the primary mutations, secondary mutations tend to be lineage-specific, (4) that the np 15257 mutation was confined to a single mtDNA lineage but may be etiologically important in some LHON cases since it was found in a LHON pedigree which lacked a common primary mutation; complete sequence analysis of the proband mtDNA revealed only a single other candidate missense mutation (at np 10663 of the ND4L gene) of uncertain pathological significance; and (5) that the np 14484 mutation may be less pathogenic than either the np 3460 or np 11778 mutations, as this mutation most commonly occurred on a single mtDNA lineage and almost always in association with secondary LHON mutations. A phylogenetic ageneous disease has thus provided key genetic data bearing on the relative pathogenicity of the LHON-associated mtDNA mutations. © 1995 Wiley-Liss, Inc.     

A simple oligonucleotide biochip capable of rapidly detecting known mitochondrial DNA mutations in Chinese patients with Leber's hereditary optic neuropathy (LHON)

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.     

继发突变位点对Leber's遗传性视神经萎缩作用机制的研究

目的探讨继发突变位点在Leber’s遗传性视神经萎缩(Leber’s hereditary optic neuropathy,LHON)疾病发生发展中的作用。方法对4个LHON家系患者及家系男性子代进行3个原发位点、24个继发位点及相邻片段检查。结果4家系均携带11778位点突变,所查患者无24个继发位点突变,但在这些位点的相邻片段上有5178、5108、3705、3721、13734等多个多态位点存在。结论线粒体多态位点具有家族遗传性,在LHON继发位点研究中应同时进行男性子代检查,以排查突变位点是否具有致病性。"修复基因"的存在可能对LHON疾病发展有影响。     

High incidence of pre-excitation syndrome in Japanese families with Leber's hereditary optic neuropathy

Cardiac conduction abnormalities have been reported in families with Leber's hereditary optic neuropathy (LHON). The pre-excitation syndrome, Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome, is reportedly common in Finns with LHON, being seen in 14 (9%) of the 163 individuals with mitochondrial DNA (mtDNA) mutations. While this syndrome is thought to be rare in other ethnic groups with LHON, the present study of 35 Japanese LHON families confirmed that it is also relatively common among Japanese families, being seen in 5 (8%) of the 63 individuals with mtDNA mutations. It remains to be determined whether the high incidence of the pre-excitation syndrome in Finnish and Japanese LHON families is due to a particular genetic composition of ethnic groups such as in Finland and in Japan, or only to a reporting bias.