仅女性发病的Leber遗传性视神经病变家系的表型分析
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摘要
目的:对仅有女性发病的11个携带m.11778G>A突变的Leber遗传性视神经病变(LHON)家系中患者的表型表现进行分析。方法:对1 362例汉族LHON患者的MT-ND4基因进行了系统的筛查,再对携带MT-ND4 11778G>A突变的11个家系进行线粒体全基因组测序及线粒体单体型分析。结果:筛查发现11个携带m.11778G>A突变的LHON家系仅累及女性母系成员。此11个家系中患者LHON外显率较低,分别为16.7%、18.8%、15.0%、6.7%、6.7%、33.3%、20.0%、16.7%、7.7%、8.3%、25.0%,平均每个家系外显率为15.90%±0.08%。LHON患者的视力损伤程度由轻度到重度不等,发病年龄7～25(12.4±4.8)岁,属于LHON的高发年龄阶段。11位先证者的线粒体单体型分别为B5a、Z、N9、B4c1b、G2h、B5a、M7b、N9a10、C7b、M7b1、M10。结论:本研究中11个携带相同m.11778G>A突变的不同家系之间,及在相同线粒体遗传背景下的同一家系中不同母系成员间LHON外显率和发病年龄都存在着显著差异,表明m.11778G>A突变是LHON发病的分子基础,但突变本身并不足以造成LHON的表型表达,提示其他修饰因子(线粒体单体型、核修饰基因及环境因素)在LHON的发生发展中发挥了一定的作用。
Objective: Phenotypic performance of 11 Leber's hereditary optic neuropathy(LHON) pedigrees carrying m.11778 G>A mutations, who had only female-onset, was analyzed. Methods: In this study we systematically screened, the MT-ND4 gene of 1 362 patients of the Chinese Han nationality with LHON.Mitochondrial genome sequencing and mitochondrial haplotype analysis were performed on 11 pedigrees carrying MT-ND4 m.11778 G>A mutation. Results: Screening revealed that 11 cases of LHON pedigrees carrying m.11778 G>A mutation only affected female maternal members. The LHON penetrance rate of these pedigrees showed low level, with 16.7%, 18.8%, 15.0%, 6.7%, 6.7%, 33.3%, 20.0%, 16.7%, 7.7%, 8.3%, 25.0% respectively. The average penetrance rate of each pedigree was 15.90%±0.08%. The degree of visual impairment in patients with LHON varied from mild to severe. The age of onset ranged from 7 to 25 years old. The average age of onset was(12.4±4.8) years old, being the high-risk age of LHON. The mitochondrial haplotype of 11 proband were B5 a, Z, N9, B4 c1 b, G2 h, B5 a, M7 b, N9 a10, C7 b, M7 b1, M10 respectively. Conclusion: In this article,there were significant differences in LHON penetrance and age of onset between 11 different pedigrees with the same m.11778 G>A mutation and different maternal members in the same mitochondrial genetic background.This suggests that m.11778 G>A mutation is the molecular basis of the pathogenesis of LHON, but the mutation itself is not sufficient to induce the phenotypic expression of LHON, suggesting that other modification factors(mitochondrial haplotypes, nuclear modifier genes and environmental factors) may play a role in the development of LHON.
Objective: Phenotypic performance of 11 Leber's hereditary optic neuropathy(LHON) pedigrees carrying m.11778 G>A mutations, who had only female-onset, was analyzed. Methods: In this study we systematically screened, the MT-ND4 gene of 1 362 patients of the Chinese Han nationality with LHON.Mitochondrial genome sequencing and mitochondrial haplotype analysis were performed on 11 pedigrees carrying MT-ND4 m.11778 G>A mutation. Results: Screening revealed that 11 cases of LHON pedigrees carrying m.11778 G>A mutation only affected female maternal members. The LHON penetrance rate of these pedigrees showed low level, with 16.7%, 18.8%, 15.0%, 6.7%, 6.7%, 33.3%, 20.0%, 16.7%, 7.7%, 8.3%, 25.0% respectively. The average penetrance rate of each pedigree was 15.90%±0.08%. The degree of visual impairment in patients with LHON varied from mild to severe. The age of onset ranged from 7 to 25 years old. The average age of onset was(12.4±4.8) years old, being the high-risk age of LHON. The mitochondrial haplotype of 11 proband were B5 a, Z, N9, B4 c1 b, G2 h, B5 a, M7 b, N9 a10, C7 b, M7 b1, M10 respectively. Conclusion: In this article,there were significant differences in LHON penetrance and age of onset between 11 different pedigrees with the same m.11778 G>A mutation and different maternal members in the same mitochondrial genetic background.This suggests that m.11778 G>A mutation is the molecular basis of the pathogenesis of LHON, but the mutation itself is not sufficient to induce the phenotypic expression of LHON, suggesting that other modification factors(mitochondrial haplotypes, nuclear modifier genes and environmental factors) may play a role in the development of LHON.
引文
[1]LEO-KOTTLER B,LUBERICHS J,BESCH D,et al.Leber’s hereditary optic neuropathy:clinical and molecular genetic results in a patient with a point mutation at np T11253C(isoleucine to threonine)in the ND4 gene and spontaneous recovery[J].Graefes Arch Clin Exp Ophthalmol,2002,240(9):758-764.
[2]QU J,WANG Y,TONG Y,et al.Leber’s hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families[J].Invest Ophthalmol Vis Sci,2010,51(10):4906-4912.
[3]孟祥娟,朱金萍,高敏,等.中国人群携带m.14484T>C突变的Leber’s遗传性视神经病变线粒体单体型及多态位点分析[J].遗传,2014,36(4):336-345.
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[5]NEUHANN T,RAUTENSTRAUSS B.Genetic and phenotypic variability of optic neuropathies[J].Expert Rev Neurother,2013,13(4):357-367.
[6]SERVIDEI S.Mitochondrial encephalomyopathies:gene mutation[J].Neuromuscul Disord,2003,13(10):848-853.
[7]梁敏,侯玲玲,姜丰,等.携带线粒体ND1基因3497C>T突变的Leber遗传性视神经病变家系临床与遗传学分析[J].温州医科大学学报,2018,48(12):859-865.
[8]MACKEY D A,OOSTRA R J,ROSENBERG T,et al.Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy[J].Am J Hum Genet,1996,59(2):481-485.
[9]RIEDER M J,TAYLOR S L,TOBE V O,et al.Automating the identification of DNA variations using quality-based fluorescence re-sequencing:analysis of the human mitochondrial genome[J].Nucleic Acids Res,1998,26(4):967-973.
[10]ANDREWS R M,KUBACKA I,CHINNERY P F,et al.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA[J].Nat Genet,1999,23(2):147.
[11]KONG Q P,BANDELT H J,SUN C,et al.Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations[J].Hum Mol Genet,2006,15(13):2076-2086.
[12]TANAKA M,CABRERA V M,GONZáLEZ A M,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan[J].Genome Res,2004,14(10A):1832-1850.
[13]杨茂林,孟思进.线粒体氧化损伤在衰老发生机制中的作用[J].医学综述,2010,16(9):1297-1300.
[14]WALLACE D C,FAN W.Energetics,epigenetics,mitochondrial genetics[J].Mitochondrion,2010,10(1):12-31.
[15]卓越,周玲娜,滕丽莎,等.线粒体单体型与线粒体相关的人类疾病[J].生物化学与生物物理进展,2016,43(11):1070-1075.
[16]BU X D,ROTTER J I.X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy:evidence from segregation analysis for dependence on X chromosome inactivation[J].Proc Natl Acad Sci U S A,1991,88(18):8198-8202.
[17]VILKKI J,OTT J,SAVONTAUS M L,et al.Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7[J].Am J Hum Genet,1991,48(3):486-491.
[18]CHEN J D,COX I,DENTON M J.Preliminary exclusion of an X-linked gene in Leber optic atrophy by linkage analysis[J].Hum Genet,1989,82(3):203-207.
[19]HUDSON G,KEERS S,YU-WAI-MAN P,et al.Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder[J].Am JHum Genet,2005,77(6):1086-1091.
[20]HUDSON G,CARELLI V,SPRUIJT L,et al.Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background[J].Am JHum Genet,2007,81(2):228-233.
[21]TORRINI A,PETROZZI M,D’URBANO L,et al.Tropeanspecific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484[J].Am JHum Genet,1997,60(50):1107-1121.
[22]CARELLI V,ACHILLI A,VALENTINO M L,et al.Haplogroup effects and recombination of mitochondrial DNA:novel clues from the analysis of Leber hereditary optic neuropathy pedigrees[J].Am J Hum Genet,2006,78(4):564-574.
[23]NEWMAN N J.Leber hereditary optic neuropathy:bad habits,bad vision?[J].Brain,2009,132(Pt 9):2306-2308.
[24]KIRKMAN M A,YU-WAI-MAN P,KORSTEN A,et al.Gene-environment interactions in Leber hereditary optic neuropathy[J].Brain,2009,132(Pt 9):2317-2326.
[25]JI Y,JIA X,LI S,et al.Evaluation of the X-linked modifier loci for Leber hereditary optic neuropathy with the G11778Amutation in Chinese[J].Mol Vis,2010,16:416-424.
[26]SHANKAR S P,FINGERT J H,CARELLI V,et al.Evidence for a novel x-linked modifier locus for leber hereditary optic neuropathy[J].Ophthalmic Genet,2008,29(1):17-24.
[27]任晓燕,陈亚茹,时雯雯,等.一个同时携带线粒体tRNAMet4435A>G和YARS2 c.5750A>C基因突变的原发性高血压家系的线粒体功能[J].温州医科大学学报,2018,48(7):479-484.
[2]QU J,WANG Y,TONG Y,et al.Leber’s hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families[J].Invest Ophthalmol Vis Sci,2010,51(10):4906-4912.
[3]孟祥娟,朱金萍,高敏,等.中国人群携带m.14484T>C突变的Leber’s遗传性视神经病变线粒体单体型及多态位点分析[J].遗传,2014,36(4):336-345.
[4]ZHANG J,ZHAO F,FU Q,et al.Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated m.14484T>C(MT-ND6)mutation in Chinese families[J].Mitochondrion,2013,13(6):772-781.
[5]NEUHANN T,RAUTENSTRAUSS B.Genetic and phenotypic variability of optic neuropathies[J].Expert Rev Neurother,2013,13(4):357-367.
[6]SERVIDEI S.Mitochondrial encephalomyopathies:gene mutation[J].Neuromuscul Disord,2003,13(10):848-853.
[7]梁敏,侯玲玲,姜丰,等.携带线粒体ND1基因3497C>T突变的Leber遗传性视神经病变家系临床与遗传学分析[J].温州医科大学学报,2018,48(12):859-865.
[8]MACKEY D A,OOSTRA R J,ROSENBERG T,et al.Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy[J].Am J Hum Genet,1996,59(2):481-485.
[9]RIEDER M J,TAYLOR S L,TOBE V O,et al.Automating the identification of DNA variations using quality-based fluorescence re-sequencing:analysis of the human mitochondrial genome[J].Nucleic Acids Res,1998,26(4):967-973.
[10]ANDREWS R M,KUBACKA I,CHINNERY P F,et al.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA[J].Nat Genet,1999,23(2):147.
[11]KONG Q P,BANDELT H J,SUN C,et al.Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations[J].Hum Mol Genet,2006,15(13):2076-2086.
[12]TANAKA M,CABRERA V M,GONZáLEZ A M,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan[J].Genome Res,2004,14(10A):1832-1850.
[13]杨茂林,孟思进.线粒体氧化损伤在衰老发生机制中的作用[J].医学综述,2010,16(9):1297-1300.
[14]WALLACE D C,FAN W.Energetics,epigenetics,mitochondrial genetics[J].Mitochondrion,2010,10(1):12-31.
[15]卓越,周玲娜,滕丽莎,等.线粒体单体型与线粒体相关的人类疾病[J].生物化学与生物物理进展,2016,43(11):1070-1075.
[16]BU X D,ROTTER J I.X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy:evidence from segregation analysis for dependence on X chromosome inactivation[J].Proc Natl Acad Sci U S A,1991,88(18):8198-8202.
[17]VILKKI J,OTT J,SAVONTAUS M L,et al.Optic atrophy in Leber hereditary optic neuroretinopathy is probably determined by an X-chromosomal gene closely linked to DXS7[J].Am J Hum Genet,1991,48(3):486-491.
[18]CHEN J D,COX I,DENTON M J.Preliminary exclusion of an X-linked gene in Leber optic atrophy by linkage analysis[J].Hum Genet,1989,82(3):203-207.
[19]HUDSON G,KEERS S,YU-WAI-MAN P,et al.Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder[J].Am JHum Genet,2005,77(6):1086-1091.
[20]HUDSON G,CARELLI V,SPRUIJT L,et al.Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background[J].Am JHum Genet,2007,81(2):228-233.
[21]TORRINI A,PETROZZI M,D’URBANO L,et al.Tropeanspecific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484[J].Am JHum Genet,1997,60(50):1107-1121.
[22]CARELLI V,ACHILLI A,VALENTINO M L,et al.Haplogroup effects and recombination of mitochondrial DNA:novel clues from the analysis of Leber hereditary optic neuropathy pedigrees[J].Am J Hum Genet,2006,78(4):564-574.
[23]NEWMAN N J.Leber hereditary optic neuropathy:bad habits,bad vision?[J].Brain,2009,132(Pt 9):2306-2308.
[24]KIRKMAN M A,YU-WAI-MAN P,KORSTEN A,et al.Gene-environment interactions in Leber hereditary optic neuropathy[J].Brain,2009,132(Pt 9):2317-2326.
[25]JI Y,JIA X,LI S,et al.Evaluation of the X-linked modifier loci for Leber hereditary optic neuropathy with the G11778Amutation in Chinese[J].Mol Vis,2010,16:416-424.
[26]SHANKAR S P,FINGERT J H,CARELLI V,et al.Evidence for a novel x-linked modifier locus for leber hereditary optic neuropathy[J].Ophthalmic Genet,2008,29(1):17-24.
[27]任晓燕,陈亚茹,时雯雯,等.一个同时携带线粒体tRNAMet4435A>G和YARS2 c.5750A>C基因突变的原发性高血压家系的线粒体功能[J].温州医科大学学报,2018,48(7):479-484.