中国人Leber遗传性视神经病变的分子遗传学和临床研究
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摘要
第一章
中国人Leber遗传性视神经病变一特殊家系的分子遗传学研究
目的:对中国汉族一缺乏三个主要原发突变位点的Leber遗传性视神经病变(Leberhereditary optic neuropathy,LHON)家系成员,进行全线粒体基因扫描,寻找可能的与疾病相关的线粒体基因突变位点。
方法:中国人LHON一家系三代共14位母系成员接受全面的眼科临床检查,包括:视力、眼底检查与照相、视野、视网膜神经纤维层厚度分析及视觉诱发电位检查;常规苯酚氯仿法提取外周血DNA,针对线粒体基因全序设计的24对引物进行PCR扩增,纯化产物由ABI 3700进行测序,与健康对照者线粒体基因全序及最新剑桥标准序列进行比对,分析可能的与疾病相关的线粒体基因突变位点。
结果:该家系表现为一典型的母系遗传病,患者无痛性视力下降和视神经萎缩的临床表现符合LHON诊断。全线粒体基因测序未发现三个主要原发突变位点,但发现存在以下线粒体基因突变:T4216C/ND_1基因、A13651G/ND_5基因和A15951G/tRNA~(Thr)基因。进一步分析表明,该家系属于亚洲人群的HaplogroupD4b1亚型。其中,T4216C突变是已报道LHON的继发突变之一,多协同LHON主要的原发突变G11778A而致病,同时又是决定欧洲人群Haplogroup J亚型的主要多态性位点;线粒体ND_5基因的A13651G突变,是决定亚洲人群Haplogroup D4a的主要多态位点,突变导致中度保守的色氨酸突变为丙氨酸,跨膜蛋白疏水性的改变,由此可能影响呼吸链复合体Ⅰ的电子传递,从而影响线粒体的氧化磷酸化;tRNA~(Thr)基因突变A15951G已报道具有协同原发突变G11778A对LHON的致病作用。
结论:本文首次报道了继发突变T4216C独立于原发突变在亚洲人群HaplogroupD4b1亚型的中国LHON家系中,也是T4216C与A13651G突变共同存在于亚洲人群HaplogroupD4b1亚型的首次报道。其与A15951G的协同作用可能在该中国人LHON家系的发病机制中具有一定的作用。但该LHON家系缺乏主要的原发突变位点,进一步提示除了线粒体基因突变外,核基因也可能与LHON的发病相关。
第二章
G11778A突变型Leber遗传性视神经病变患者血清总SOD活力和MDA含量的研究
目的:通过检测G11778A突变型Leber遗传性视神经病变(LHON)患者血清总超氧化物歧化酶(SOD)活力和丙二醛(MDA)含量,了解LHON患者体内氧化-抗氧化状态。
方法:本研究为病例-对照研究,纳入了经眼科检查和线粒体基因测序确诊的G11778A突变型LHON患者19例、携带者12例,以及正常对照者30例,分别应用黄嘌呤氧化酶法和硫代巴比妥酸法检测受试者血清总SOD活力和MDA含量。
结果:LHON患者血清总SOD活力较携带者和正常对照者均明显下降(q分别为7.085、8.351,均P＜0.05),携带者与正常对照者的血清总SOD活力差异无统计学意义(q=0.269,P＞0.05)。LHON患者和携带者的血清MDA含量均明显高于正常对照者(q分别为9.069、4.748,均P＜0.05),LHON患者的血清MDA含量也高于携带者(q=3.618,P＜0.05)。
结论:LHON患者体内抗氧化能力明显下降,机体氧化-抗氧化系统失衡与LHON的发病有关。
第三章
StratusOCT在Leber遗传性视神经病变视网膜神经纤维层厚度分析中的应用
目的:应用StratusOCT测量Leber遗传性视神经病变(LHON)患者和携带者的视网膜神经纤维层(Retinal nerve fiber layer,RNFL)厚度,以了解LHON患者和携带者的RNFL厚度特点和变化规律。
方法:本研究纳入了经临床和线粒体全基因扫描确诊的G11778A突变型LHON母系家庭成员21例(41眼),正常对照者136例(209眼)。根据病史和视功能检查,将LHON家系成员初步划分为携带者和LHON患者;根据其眼底表现,进一步划分为正常携带者、临床前期者、早期、进展期和晚期患者。所有受试者均接受了StratusOCT检查,采用的检查程序是以视盘为中心直径3.4mm的快速RNFL厚度测量程序。
结果:眼底表现正常的LHON携带者的RNFL厚度与正常对照者相比无明显差异;临床前期者和LHON早期患者的颞侧、上方、下方RNFL厚度,以及360°平均RNFL厚度均较正常对照者增厚;进展期患者RNFL表现为仅颞侧变薄;晚期患者RNFL则表现为所有象限均明显变薄。
结论:应用StratusOCT测量RNFL厚度,有助于了解LHON携带者和患者的RNFL厚度特点和变化规律,能够客观反映LHON疾病发生发展过程中RNFL的改变。将LHON病程分为早期、进展期和晚期的临床分期法,能够更准确地反映LHON的自然病程,并与其眼底改变相符合。对处于临床前期者的随访有可能发现LHON发病的扳机点,以利于将来可能开展的早期干预和治疗。
Molecular genetic study of a Chinese pedigree of Leber hereditary optic neuropathy
Purpose:Clinical and genetic study of a four-generation Han Chinese family with Leber hereditary optic neuropathy(LHON) lacking the common primary mutations,and analyze the possible mitochondrial DNA(mtDNA) mutations associated with LHON in this family.
Methods:Ophthalmic examinations of patients in the Chinese LHON family were conducted.Genomic DNA was isolated from the whole blood of participants,sequence analysis of the complete mitochondrial genome was performed,and compared with control subjects and the latest updated revised Cambridge Reference Sequence.
Results:Patients in this Chinese LHON family showed typical clinical features of LHON.Routine genetic analysis did not found any reported primary LHON mutations. Sequence analysis of the entire mtDNA found the secondary mutation T4216C in the ND_1 gene,which also determines the Caucasian haplogroup J;the mutation A13651G in the ND_5 gene,leading to a moderately conserved threonine changed by alanine;the reported mutation A15951G in the tRNA~(Thr) gene was also found in this family. Conclusions:This is the first report that the secondary mutation T4216C occurred independently from primary mutations in a Chinese LHON pedigree,and it is the first report that the concomitant mutations T4216C/ND_1 and the A 13651G/ND_5 occur in the context of the Asian haplogroup D4b1,the co-inheritance of T4216C,A13651G and A15951G mutations increase the probability of LHON.However,as none of primary mutations has been identified,mtDNA variants alone can not explain the pathogenic mechanism of this special LHON pedigree,it is strongly suggested that nuclear modifier genes most likely paly an important role on the penetrance of the disease.
PARTⅡ
Evaluation of the serum levels of SOD and MDA in patients with Leber hereditary optic neuropathy carrying the mitochondrial DNA G11778A mutation
Purpose:To determine the serum levels of total superoxide dismutase(SOD) activity and malondialdehyde(MDA),and evaluate the oxidant-antioxidant status in patients with Leber hereditary optic neuropathy(LHON) carrying the mitochondrial G11778A mutation.
Methods:19 patients and 12 carriers from three Chinese G11778A LHON families were enrolled in this study,and 30 age-matched healthy volunteers were recruited as normal controls.The serum levels of total SOD activity and MDA in all subjects were measured by Xanthine oxidase test and Thiobarbituric acid technique,respectively.
Results:The serum level of total SOD activity in LHON patients was significantly less than those in carders and normal controls(q=7.085 and 8.351,respectively,both P＜0.01),however,there was no significant difference between the carriers and normal controls(q=0.269,P＞0.05).The serum level of MDA in patients and carders was significantly higher than that in normal controls(q=9.069 and 4.748,respectively,both P＜0.01),and it was also significantly higher in patients than that in carriers(q=3.618, P＜0.05).
Conclusions:Antioxidant capacity decreased evidently in patients with LHON,which supported that the onset of LHON was related with oxidation-antioxidation imbalance.
PARTⅢ
Retinal nerve fiber layer analysis by optical coherence tomography in different stages of Leber hereditary optic neuropathy
Purpose:To study the retinal nerve fiber layer(RNFL) thickness in different clinical stages of Leber hereditary optic neuropathy(LHON) by optical coherence tomography (StratusOCT),and discuss the classification of LHON.
Methods:21 maternal family members(41 eyes) from three Chinese LHON families and 136 age-matched healthy controls(209 eyes) were invited to the study.The fast RNFL thickness(3.4) scan acquisition protocol was used to assess the thickness of RNFL by StratusOCT.
Results:Eyes with unaffected carriers showed normal fundus and normal RNFL thickness;eyes with the presymptomatic and the early LHON showed a thicker RNFL in the temporal,superior,inferior quadrants and the 360°average measuremen;eyes with progressive LHON showed a thinner RNFL in the temporal quadrant only;eyes with atrophy LHON revealed a thinner RNFL in all quadrants.
Conclusions:According to clinical features and verified by StratusOCT,maternal family memebers were divided into five subgroups:the unaffected carrier,and the presymptomatic,early,progressive,atrophic LHON.RNFL thickness analysis by StratusOCT is helpfor to detect the pathogenic changes of LHON,such classification of LHON may be the best description of the natural pathologic process of LHON,and may be helpful for further study of LHON.
中国人Leber遗传性视神经病变一特殊家系的分子遗传学研究
目的:对中国汉族一缺乏三个主要原发突变位点的Leber遗传性视神经病变(Leberhereditary optic neuropathy,LHON)家系成员,进行全线粒体基因扫描,寻找可能的与疾病相关的线粒体基因突变位点。
方法:中国人LHON一家系三代共14位母系成员接受全面的眼科临床检查,包括:视力、眼底检查与照相、视野、视网膜神经纤维层厚度分析及视觉诱发电位检查;常规苯酚氯仿法提取外周血DNA,针对线粒体基因全序设计的24对引物进行PCR扩增,纯化产物由ABI 3700进行测序,与健康对照者线粒体基因全序及最新剑桥标准序列进行比对,分析可能的与疾病相关的线粒体基因突变位点。
结果:该家系表现为一典型的母系遗传病,患者无痛性视力下降和视神经萎缩的临床表现符合LHON诊断。全线粒体基因测序未发现三个主要原发突变位点,但发现存在以下线粒体基因突变:T4216C/ND_1基因、A13651G/ND_5基因和A15951G/tRNA~(Thr)基因。进一步分析表明,该家系属于亚洲人群的HaplogroupD4b1亚型。其中,T4216C突变是已报道LHON的继发突变之一,多协同LHON主要的原发突变G11778A而致病,同时又是决定欧洲人群Haplogroup J亚型的主要多态性位点;线粒体ND_5基因的A13651G突变,是决定亚洲人群Haplogroup D4a的主要多态位点,突变导致中度保守的色氨酸突变为丙氨酸,跨膜蛋白疏水性的改变,由此可能影响呼吸链复合体Ⅰ的电子传递,从而影响线粒体的氧化磷酸化;tRNA~(Thr)基因突变A15951G已报道具有协同原发突变G11778A对LHON的致病作用。
结论:本文首次报道了继发突变T4216C独立于原发突变在亚洲人群HaplogroupD4b1亚型的中国LHON家系中,也是T4216C与A13651G突变共同存在于亚洲人群HaplogroupD4b1亚型的首次报道。其与A15951G的协同作用可能在该中国人LHON家系的发病机制中具有一定的作用。但该LHON家系缺乏主要的原发突变位点,进一步提示除了线粒体基因突变外,核基因也可能与LHON的发病相关。
第二章
G11778A突变型Leber遗传性视神经病变患者血清总SOD活力和MDA含量的研究
目的:通过检测G11778A突变型Leber遗传性视神经病变(LHON)患者血清总超氧化物歧化酶(SOD)活力和丙二醛(MDA)含量,了解LHON患者体内氧化-抗氧化状态。
方法:本研究为病例-对照研究,纳入了经眼科检查和线粒体基因测序确诊的G11778A突变型LHON患者19例、携带者12例,以及正常对照者30例,分别应用黄嘌呤氧化酶法和硫代巴比妥酸法检测受试者血清总SOD活力和MDA含量。
结果:LHON患者血清总SOD活力较携带者和正常对照者均明显下降(q分别为7.085、8.351,均P＜0.05),携带者与正常对照者的血清总SOD活力差异无统计学意义(q=0.269,P＞0.05)。LHON患者和携带者的血清MDA含量均明显高于正常对照者(q分别为9.069、4.748,均P＜0.05),LHON患者的血清MDA含量也高于携带者(q=3.618,P＜0.05)。
结论:LHON患者体内抗氧化能力明显下降,机体氧化-抗氧化系统失衡与LHON的发病有关。
第三章
StratusOCT在Leber遗传性视神经病变视网膜神经纤维层厚度分析中的应用
目的:应用StratusOCT测量Leber遗传性视神经病变(LHON)患者和携带者的视网膜神经纤维层(Retinal nerve fiber layer,RNFL)厚度,以了解LHON患者和携带者的RNFL厚度特点和变化规律。
方法:本研究纳入了经临床和线粒体全基因扫描确诊的G11778A突变型LHON母系家庭成员21例(41眼),正常对照者136例(209眼)。根据病史和视功能检查,将LHON家系成员初步划分为携带者和LHON患者;根据其眼底表现,进一步划分为正常携带者、临床前期者、早期、进展期和晚期患者。所有受试者均接受了StratusOCT检查,采用的检查程序是以视盘为中心直径3.4mm的快速RNFL厚度测量程序。
结果:眼底表现正常的LHON携带者的RNFL厚度与正常对照者相比无明显差异;临床前期者和LHON早期患者的颞侧、上方、下方RNFL厚度,以及360°平均RNFL厚度均较正常对照者增厚;进展期患者RNFL表现为仅颞侧变薄;晚期患者RNFL则表现为所有象限均明显变薄。
结论:应用StratusOCT测量RNFL厚度,有助于了解LHON携带者和患者的RNFL厚度特点和变化规律,能够客观反映LHON疾病发生发展过程中RNFL的改变。将LHON病程分为早期、进展期和晚期的临床分期法,能够更准确地反映LHON的自然病程,并与其眼底改变相符合。对处于临床前期者的随访有可能发现LHON发病的扳机点,以利于将来可能开展的早期干预和治疗。
Molecular genetic study of a Chinese pedigree of Leber hereditary optic neuropathy
Purpose:Clinical and genetic study of a four-generation Han Chinese family with Leber hereditary optic neuropathy(LHON) lacking the common primary mutations,and analyze the possible mitochondrial DNA(mtDNA) mutations associated with LHON in this family.
Methods:Ophthalmic examinations of patients in the Chinese LHON family were conducted.Genomic DNA was isolated from the whole blood of participants,sequence analysis of the complete mitochondrial genome was performed,and compared with control subjects and the latest updated revised Cambridge Reference Sequence.
Results:Patients in this Chinese LHON family showed typical clinical features of LHON.Routine genetic analysis did not found any reported primary LHON mutations. Sequence analysis of the entire mtDNA found the secondary mutation T4216C in the ND_1 gene,which also determines the Caucasian haplogroup J;the mutation A13651G in the ND_5 gene,leading to a moderately conserved threonine changed by alanine;the reported mutation A15951G in the tRNA~(Thr) gene was also found in this family. Conclusions:This is the first report that the secondary mutation T4216C occurred independently from primary mutations in a Chinese LHON pedigree,and it is the first report that the concomitant mutations T4216C/ND_1 and the A 13651G/ND_5 occur in the context of the Asian haplogroup D4b1,the co-inheritance of T4216C,A13651G and A15951G mutations increase the probability of LHON.However,as none of primary mutations has been identified,mtDNA variants alone can not explain the pathogenic mechanism of this special LHON pedigree,it is strongly suggested that nuclear modifier genes most likely paly an important role on the penetrance of the disease.
PARTⅡ
Evaluation of the serum levels of SOD and MDA in patients with Leber hereditary optic neuropathy carrying the mitochondrial DNA G11778A mutation
Purpose:To determine the serum levels of total superoxide dismutase(SOD) activity and malondialdehyde(MDA),and evaluate the oxidant-antioxidant status in patients with Leber hereditary optic neuropathy(LHON) carrying the mitochondrial G11778A mutation.
Methods:19 patients and 12 carriers from three Chinese G11778A LHON families were enrolled in this study,and 30 age-matched healthy volunteers were recruited as normal controls.The serum levels of total SOD activity and MDA in all subjects were measured by Xanthine oxidase test and Thiobarbituric acid technique,respectively.
Results:The serum level of total SOD activity in LHON patients was significantly less than those in carders and normal controls(q=7.085 and 8.351,respectively,both P＜0.01),however,there was no significant difference between the carriers and normal controls(q=0.269,P＞0.05).The serum level of MDA in patients and carders was significantly higher than that in normal controls(q=9.069 and 4.748,respectively,both P＜0.01),and it was also significantly higher in patients than that in carriers(q=3.618, P＜0.05).
Conclusions:Antioxidant capacity decreased evidently in patients with LHON,which supported that the onset of LHON was related with oxidation-antioxidation imbalance.
PARTⅢ
Retinal nerve fiber layer analysis by optical coherence tomography in different stages of Leber hereditary optic neuropathy
Purpose:To study the retinal nerve fiber layer(RNFL) thickness in different clinical stages of Leber hereditary optic neuropathy(LHON) by optical coherence tomography (StratusOCT),and discuss the classification of LHON.
Methods:21 maternal family members(41 eyes) from three Chinese LHON families and 136 age-matched healthy controls(209 eyes) were invited to the study.The fast RNFL thickness(3.4) scan acquisition protocol was used to assess the thickness of RNFL by StratusOCT.
Results:Eyes with unaffected carriers showed normal fundus and normal RNFL thickness;eyes with the presymptomatic and the early LHON showed a thicker RNFL in the temporal,superior,inferior quadrants and the 360°average measuremen;eyes with progressive LHON showed a thinner RNFL in the temporal quadrant only;eyes with atrophy LHON revealed a thinner RNFL in all quadrants.
Conclusions:According to clinical features and verified by StratusOCT,maternal family memebers were divided into five subgroups:the unaffected carrier,and the presymptomatic,early,progressive,atrophic LHON.RNFL thickness analysis by StratusOCT is helpfor to detect the pathogenic changes of LHON,such classification of LHON may be the best description of the natural pathologic process of LHON,and may be helpful for further study of LHON.
引文
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