中国Leber遗传性视神经病变G11696A突变两个家系分析

目的对两个中国Leber遗传性视神经病变(Leber’shereditary optic neuropathy,LHON)家系的临床和分子遗传学特征进行分析。方法眼科临床检查发现在这两个家系中只有先证者1人出现视力障碍,发病年龄分别为10岁和17岁。对这两个家系先证者使用24对有部分重叠的引物进行线粒体DNA(mitochondrial DNA,mtDNA)全序列扩增分析。结果没有发现mtDNAG11778A、G3460A和T14484C3个常见的突变位点,而发现了与LHON相关的ND4G11196A同质性突变位点的存在,在167名正常对照只发现1例G11696A突变。结论线粒体DNA全序列分析发现两个家系呈现独特的mtDNA多态性,都属于东亚单体型D4。不完全外显率和正常对照频率(1/167)表明G11696A突变本身不足以导致LHON的发生,说明其它因素在这两个LHON家系的表型表达中也起一定的作用。在这些家系mtDNA中缺乏影响重要功能突变位点的存在,排除了线粒体背景对LHON临床表型的影响。因此,核修饰基因、环境因素可能对两个中国G11696A突变家系的外显率和发病严重程度起促进作用。     

线粒体单倍型对Leber病的影响

在Leber遗传性视神经病变(Leber's hereditary optic neuropathy,LHON)家系中由母系传递这种视觉功能障碍,提示线粒体基因组(mitochondrial DNA,mtDNA)突变为该疾病发生的主要分子基础.在不同种族人群的LHON家系中,有50%以上是由于mtDNA编码呼吸链复合体I上ND1 G4360A,ND4 G11778A和ND6 T14484C突变引起的.这3个突变位点因为致病率高,被称为原发性突变.但是携带这些位点突变的母系成员并不是都会出现LHON症状,而且在同一个家系内或不同家系间携带相同mtDNA突变的患者在发病年龄、视力损伤程度和发病过程也都不完全一样.这提示可能这些LHON相关的原发性突变本身不足以导致临床表现.IMON的男性多发、不完全外显和不同的基因表现度表明还有其他因素在疾病的发生发展过程起到修饰作用,这些因素包括:个人因素、环境因素、核修饰基因和mtDNA单倍型.特别是mtDNA单倍型,在对携带3个LHON相关原发性突变的家系中母系成员的发病起到协同作用.     

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遗传性视神经病变分子遗传学研究进展

Leber遗传性视神经病变(Leber hereditary optic neuropathy, LHON) 是一种导致双眼快速的、无痛性的中心视力丧失的母系遗传性疾病。主要是由线粒体DNA（mitochondrial DNA,mtDNA）发生点突变所致。本文主要介绍LHON原发性、继发性和其它相关位点突变,阐述核修饰基因、mtDNA单倍型及环境因素（吸烟、饮酒等）对LHON外显率和发病严重程度的影响。     

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.     

Leber遗传性视神经病变线粒体DNA突变的研究

目的 探讨Leber遗传性视神经病变患者的线粒体DNA突变类型及特点.方法 分别应用等位基因特异性PCR（MSP-PCR）、聚合酶链反应-限制性片段长度多态性（PCR-RFLP）和聚合酶链反应-单链构象多态性（PCR-SSCP）联合DNA测序的方法,对12个家系中21位临床症状疑诊为LHON的患者及其19位无明显眼疾的母系亲属进行线粒体DNA检测.结果 40例受检者中35例发生11778位点突变,2位成员有3460位点突变,有1例发现有4258位点突变（A→G）.结论 11778是LHON患者常见的突变位点,3460突变少见,新发现的突变位点4258可能是新的继发突变或基因多态性.     

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.     

Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation

We report here the clinical, genetic and molecular characterization of four Han Chinese families with Leber's hereditary optic neuropathy (LHON). The penetrances of optic neuropathy in these Chinese pedigrees were 38%, 38%, 44% and 56%. This observation is in contrast with the previously identified 14 Chinese families with very low penetrance of LHON. The age-at-onset for visual impairment in matrilineal relatives in these Chinese families varied from 18 to 30 years. Furthermore, the ratios between affected male and female matrilineal relatives in these families were 3:0, 3:0, 3:1 and 2:3, respectively. Molecular analysis of mitochondrial genomes identified the known ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M9a. Of these, the ND1 T3394C mutation caused the substitution of a highly conserved histidine for tyrosine (Y30H) at amino acid position 30. This mutation was associated with LHON in other families with low penetrance of optic neuropathy and other clinical abnormalities. The presence of both G11778A and T3394C mutations appears to contribute to higher penetrance of optic neuropathy in these four Chinese families than other Chinese families carrying only the G11778A mutation. Therefore, the mitochondrial haplogroup M9a specific variant T3394C may modulate the phenotypic manifestation of LHON-associated G11778A mutation in these Chinese pedigrees.     

山西地区线粒体DNA11778突变所致Leber遗传性视神经病变外显率分析

目的　分析山西地区线粒体 DNA11778位点突变者外显率。方法　应用等位基因特异性PCR检测视神经病变者线粒体DNA11778位点 ,对突变者及其母系成员进行分析。结果　在 30个家系中 17个家系仅先证者患病 ,另 13个家系除先证者外母系亲属有 72人携带该位点突变 ,其中 4 0人出现临床症状。结论　山西地区线粒体 DNA11778位点突变者外显率达 5 5 .6 %。     

Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy

We report the molecular epidemiology of three primary mutations in mitochondrial DNA (mtDNA) responsible for Leber hereditary optic neuropathy (LHON) based on analysis of probands suspected with LHON from 903 Chinese families. Most of them had optic neuropathy of unknown cause, and only 128 had a family history of optic neuropathy. Mutations in the mtDNA were detected in 346 probands. Of the 346 cases, 340 were homoplasmic and only six were heteroplasmic; 284 were male and 62 were female; 120 had a family history and 226 were sporadic. G11778A, T14484C and G3460A mutations were detected in 312 (90.2%), 30, and four families, respectively. The majority (226/346, 65.3%) of all LHON cases in Chinese are sporadic. These 226 probands (29.2%) were identified from 775 probands with sporadic optic neuropathy. Affected male-to-female ratio was 4.6:1 for all probands but was 2.2:1 for family members. Average age at onset was 18.5 years, ranging from 4.5 to 47 years old.     

Pediatric-Onset Dystonia Associated with Bilateral Striatal Necrosis and G14459A Mutation in a Korean Family: A Case Report

We describe a Korean family presenting with pediatric-onset, progressive, generalized dystonia with bilateral striatal necrosis and the homoplasmic G14459A mutation in the mitochondrial ND6 gene. The G14459A mutation has been reported in families presenting with Leber hereditary optic neuropathy (LHON) alone, LHON plus dystonia, or pediatric-onset dystonia. The proband had shown dysarthria, progressive generalized dystonia, and spasticity at 5 yr. Brain MRI demonstrated bilateral striatal necrosis. Additional investigation of family members revealed the presence of homoplasmic G14459A mutation in asymptomatic individuals. The clinical manifestation of the homoplasmic G14459A mtDNA mutation within the same family showed asymptomatic or pediatric-onset dystonia, without optic neuropathy. This study reemphasizes that the G14459A mutation is a candidate mutation for maternally inherited dystonia, regardless of optic neuropathy, and supports the hypothesis that nuclear genes may play a role in modifying the clinical expression of mitochondrial disease.     

A mutation of mitochondrial DNA in Japanese families with Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by optic nerve degeneration associated with severe bilateral visual loss in young men and occasionally in women. A mitochondrial DNA (mtDNA) replacement mutation in LHON patient, G to A transition at nucleotide position (nt) 11778 converting the 340th arginine to histidine in the NADH dehydrogenase subunit 4, was detected as SfaNI site polymorphism (Wallace et al., Science, 242: 1427-1430, 1988). To evaluate if the SfaNI site loss can be used to diagnose LHON patients, mtDNAs from peripheral blood of six affected males including five probands from five unrelated Japanese families with LHON, a pair of parents and a normal sister of one of the probands and 4 control persons were analyzed using PCR amplification method. The mutation of leukocyte mtDNA at nt 11778 was identified in all of the affected patients, the normal mother and the sister examined, while the father who is normal and 4 control persons did not show the change. These findings support that the mutation at nt 11778 is also associated with LHON in the Japanese and the test of the SfaNI site loss described here is useful for confirming the clinical diagnosis of LHON patients with the mutation at nt 11778.     

A mutation of mitochondrial DNA in Japanese families with Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by optic nerve degeneration associated with severe bilateral visual loss in young men and occasionally in women. A mitochondrial DNA (mtDNA) replacement mutation in LHON patient, G to A transition at nucleotide position (nt) 11778 converting the 340th arginine to histidine in the NADH dehydrogenase subunit 4, was detected asSfaNI site polymorphism (Wallaceet al., Science,242: 1427–1430, 1988). To evaluate if theSfaNI site loss can be used to diagnose LHON patients, mtDNAs from peripheral blood of six affected males including five probands from five unrelated Japanese families with LHON, a pair of parents and a normal sister of one of the probands and 4 control persons were analyzed using PCR amplification method. The mutation of leukocyte mtDNA at nt 11778 was identified in all of the affected patients, the normal mother and the sister examined, while the father who is normal and 4 control persons did not show the change. These findings support that the mutation at nt 11778 is also associated with LHON in the Japanese and the test of theSfaNI site loss described here is useful for confirming the clinical diagnosis of LHON patients with the mutation at nt 11778.     

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。     

A patient with two mitochondrial DNA mutations causing PEO and LHON

We report a 22-year-old man with PEO and optic atrophy. PEO developed before the onset of optic atrophy. The patient showed mitochondrial myopathy with cytochrome c oxidase deficient fibers.In skeletal muscle the patient was homoplasmic for the mtDNA G11778A Leber hereditary optic neuropathy (LHON) mutation and heteroplasmic for the mtDNA 5 kb “common” deletion mutation. In blood only the homoplasmic LHON mutation was identified.The occurrence of two pathogenic mtDNA mutations is exceedingly rare. The clinical findings in this patient indicate that the combination of the two mtDNA mutations resulted in the expected combined phenotype since the mtDNA deletion mutation accounted for the PEO and the mtDNA G11778A point mutation for the optic atrophy.     

Clinical variability in maternally inherited leber hereditary optic neuropathy with the G14459A mutation

Spasticity and dystonia have been associated with mitochondrial (mt) DNA mutations at A11696G, G14459A, and T14596A. We describe the clinical features and molecular analysis of two Caucasian pedigrees with the 14,459 guanosine (G) --> adenine (A) transition. The maternally inherited Leber hereditary optic neuropathy (LHON) phenotypes showed extreme clinical variability and the only screening test that was abnormal in the patient with spasticity/dystonia was a high T2 signal in the putamen bilaterally. The male patient in the second pedigree showed features of optic neuropathy without spasticity/dystonia. These results further support that the 14,459 G --> A transition mutation is causally related to LHON and spasticity/dystonia.