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
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摘要
线粒体ND6基因(MT-ND6)上的m.14484T>C突变是Leber’s遗传性视神经病变(Leber’s hereditary optic neuropathy,LHON)的一个原发性突变,但该突变自身不足以产生视力损伤。为研究线粒体单体型对携带该突变人群LHON发病的影响,文章对1 177例中国汉族LHON患者MT-ND6基因进行了全面系统的筛查,共筛查到67例患者携带m.14484T>C同质性突变,在该研究群体中所占比例为5.7%。携带m.14484T>C突变的51例家系LHON的外显率从5.6%~100.0%不等,平均外显率为21.5%。对家系中51例先证者线粒体全基因组进行分析,各表现为不同的多态性,分别属于18个东亚线粒体单体型。其中单体型A和单体型F在病例组频率均明显低于106例对照组。另外,单体型M10a在病例组中占9.8%,在对照组中未被发现,进一步发现该单体型家系LHON的平均外显率(46.13%)显著高于其他单体型家系的平均外显率,提示线粒体单体型M10a可能增加视力损伤的风险。
The m.14484T>C mutation in mitochondrial ND6 gene(MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy(LHON), but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were significantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average penetrance(46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those carrying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss.
The m.14484T>C mutation in mitochondrial ND6 gene(MT-ND6) is a primary mutation underlying the development of Leber's hereditary optic neuropathy(LHON), but by itself not enough to cause visual loss. To explore the role of mitochondrial haplogroups on the expression of LHON for the people carrying the m.14484T>C mutation, we performed systematic and extended mutational screening of MT-ND6 gene in a cohort of 1177 Han Chinese patients with LHON. A total of 67 affected subjects carried the homoplasmic m.14484T>C mutation, accounting for 5.7% of this LHON population. The penetrances of optic neuropathy among 51 pedigrees carrying the m.14484T>C mutation ranged from 5.6% to 100.0%, with the average of 21.5%. The sequence analysis of entire mitochondrial genomes of 51 probands exhibited distinct sets of polymorphisms belonging to 18 Eastern Asian haplogroups. The frequencies of haplogroup A and haplogroup F were significantly less in the LHON mtDNA samples than those in 106 Chinese controls. On the other hand, the haplogroup M10a accounted for 9.8% of the patient's mtDNA samples but was absent in 106 Chinese controls. Strikingly, the average penetrance(46.13%) of optic neuropathy for the pedigrees carrying mitochondrial haplogroup M10a was higher than those carrying other mtDNA haplogroups. These observations indicated that mitochondrial haplogroup M10a may increase the risk of visual loss.
引文
[1]Yu-Wai-Man P,Griffiths PG,Hudson G,Chinnery PF.Inherited mitochondrial optic neuropathies.J Med Genet,2009,46(3):145–158.
[2]王燕,郭向明,贾小云,黎仕强,肖学珊,郭莉,张清炯.中国人Leber遗传性视神经病变的原发突变及临床特征.中华医学遗传学杂志,2005,22(3):334–336.
[3]Qu J,Zhou X,Zhao F,Liu X,Zhang M,Sun YH,Liang M,Yuan M,Liu Q,Tong Y,Wei QP,Yang L,Guan MX.Low penetrance of Leber's hereditary optic neuropathy in ten Han Chinese families carrying the ND6 T11484C mutation.Biochim Biophys Acta,2010,1800(3):305–312.
[4]Wallace DC,Singh G,Lott MT,Hodge JA,Schurr TG,Lezza AM,Elsas LJ 2nd,Nikoskelainen EK.Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy.Science,1988,242(4884):1427–1430.
[5]MITOMAP:A Human Mitochondrial Genome Database.http://www.mitomap.org,2009.
[6]Zhang M,Zhou X,Li C,Zhao F,Zhang J,Yuan M,Sun YH,Wang J,Tong Y,Liang M,Yang L,Cai W,Wang L,Qu J,Guan MX.Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4G11778A mutation.Mol Gene Metab,2010,101(2–3):192–199.
[7]Zhou X,Qian Y,Zhang J,Tong Y,Jiang P,Liang M,Dai X,Zhou H,Zhao F,Ji Y,Mo JQ,Qu J,Guan MX.Leber's hereditary optic neuropathy is associated with the T3866Cmutation in mitochondrial ND1 gene in three Han Chinese Families.Invest Ophthalmol Vis Sci,2012,53(8):4586–4594.
[8]Qu J,Li RH,Zhou XT,Tong Y,Lu F,Qian YP,Hu YW,Mo JQ,West CE,Guan MX.The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation.Invest Ophthalmol Vis Sci,2006,47(2):475–483.
[9]周晖晖,戴显宁,林蓓,米慧,刘晓玲,赵福新,张娟娟,周翔天,孙艳红,韦企平,瞿佳,管敏鑫.7例携带线粒体tRNAAla C5601T突变的Leber遗传性视神经病变家系的相关研究.遗传,2012,34(8):1031–1042.
[10]Qu J,Li R,Zhou X,Tong Y,Yang L,Chen J,Zhao F,Lu C,Qian Y,Lu F,Guan MX.Cosegregation of the ND4G11696A mutation with the LHON-associated ND4G11778A mutation in a four generation Chinese family.Mitochondrion,2007,7(1–2):140–146.
[11]冀延春,刘晓玲,赵福新,张娟娟,章豫,周翔天,瞿佳,管敏鑫.线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点.遗传,2011,33(4):322–328.
[12]Zhang JJ,Zhou XT,Zhou J,Li CW,Zhao FX,Wang Y,Meng YZ,Wang JY,Yuan MX,Cai WS,Tong Y,Sun YH,Yang L,Qu J,Guan MX.Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHONassociated G11778A mutation in four Chinese families.Biochem Biophys Res Commun,2010,399(4):647–653.
[13]Tong Y,Mao Y,Zhou X,Yang L,Zhang J,Cai W,Zhao F,Wang X,Lu F,Qu J,Guan MX.The mitochondrial tRNAGlu A14693G mutation may influence the phenotypic manifestation of ND1 G3460A mutation in a Chinese family with Leber’s hereditary optic neuropathy.Biochem Biophys Res Commun,2007,357(2):524–530.
[14]张永梅,冀延春,刘晓玲,周翔天,赵福新,孙艳红,韦企平,张娟娟,刘燕,瞿佳,管敏鑫.线粒体tRNAGluA14693G可能是与Leber遗传性视神经病变相关的基因突变.遗传,2010,32(4):353–359.
[15]Li RH,Qu J,Zhou XT,Tong Y,Hu YW,Qian YP,Lu F,Mo JQ,West CE,Guan MX.The mitochondrial tRNAThrA15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family.Gene,2006,376(1):79–86.
[16]Newman N J.Leber hereditary optic neuropathy:bad habits,bad vision.Brain,2009,132(Pt 9):2306–2308.
[17]Kirkman MA,Yu-Wai-Man P,Korsten A,Leonhardt M,Dimitriadis K,De Coo IF,Klopstock T,Chinnery PF.Gene environment interactions in Leber hereditary optic neuropathy.Brain,2009,132(Pt 9):2317–2326.
[18]Charlmers RM,Harding AE.A case-control study of Leber’s hereditary optic neuropathy.Brain,1996,119(Pt 5):1481–1486.
[19]Hudson G,Carelli V,Spruijt L,Gerards M,Mowbray C,Achilli A,Pyle A,Elson J,Howell N,La Morgia C,Valentino ML,Huoponen K,Savontaus ML,Nikoskelainen E,Sadun AA,Salomao SR,Belfort R Jr,Griffiths P,Man PY,de Coo RF,Horvath R,Zeviani M,Smeets HJ,Torroni A,Chinnery PF.Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.Am J Hum Genet,2007,81(2):228–233.
[20]Ji Y,Zhang AM,Jia X,Zhang YP,Xiao X,Li S,Guo X,Bandelt HJ,Zhang Q,Yao YG.Mitochondrial DNA haplogroups M7b1’2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese familieswith the m.11778G-->A mutation.Am J Hum Genet,2008,83(6):760–768.
[21]Brown MD,Torroni A,Reckord CL,Wallace DC.Phy-logenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent oc-currences of the common mutations.Hum Mutat,1995,6(4):311–325.
[22]Rieder MJ,Taylor SL,Tobe VO,Nickerson DA.Automating the identification of DNA variations using quality-based fluorescence re-sequencing:analysis of the human mitochondrial genome.Nucleic Acids Res,1998,26(4):967–973.
[23]Andrews RM,Kubacka I,Chinnery PF,Lightowlers RN,Turnbull DM,Howell N.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet,1999,23(2):147.
[24]Tanaka M,Cabrera VM,González AM,Larruga JM,Takeyasu T,Fuku N,Guo LJ,Hirose R,Fujita Y,Kurata M,Shinoda K,Umetsu K,Yamada Y,Oshida Y,Sato Y,Hattori N,Mizuno Y,Arai Y,Hirose N,Ohta S,Ogawa O,Tanaka Y,Kawamori R,Shamoto-Nagai M,Maruyama W,Shimokata H,Suzuki R,Shimodaira H.Mitochondrial genome variation in eastern Asia and the peopling of Japan.Genome Res,2004,14(10A):1832–1850.
[25]Kong QP,Bandelt HJ,Sun C,Yao YG,Salas A,Achilli A,Wang CY,Zhong L,Zhu CL,Wu SF,Torroni A,Zhang YP.Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations.Hum Mol Genet,2006,15(13):2076–2086.
[26]Kaewsutthi S,Phasukkijwatana N,Joyjinda Y,Chuenkongkaew W,Kunhapan B,Tun AW,Suktitipat B,Lertrit P.Mitochondrial haplogroup background may influenceSoutheast Asian G11778A Leber hereditary optic neuropathy.Invest Ophthalmol Vis Sci,2011,52(7):4742–4748.
[27]Phasukkijwatana N,Kunhapan B,Stankovich J,Chuenkongkaew WL,Thomson R,Thornton T,Bahlo M,Mushiroda T,Nakamura Y,Mahasirimongkol S,Tun AW,Srisawat C,Limwongse C,Peerapittayamongkol C,Sura T,Suthammarak W,Lertrit P.Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand.Hum Genet,2010,128(1):39–49.
[28]Zhang AM,Jia X,Zhang QJ,Yao YG.No association between the SNPs(rs3749446 and rs1402000)in the PARL gene and LHON in Chinese patients with m.11778G>A.Hum Genet,2010,128(4):465–468.
[29]Ji Y,Jia X,Li S,Xiao X,Guo X,Zhang Q.Evaluation of the X-linked modifier loci for Leber hereditary optic neuropathy with the G11778A mutation in Chinese.Mol Vis,2010,16(47):416–424.
[2]王燕,郭向明,贾小云,黎仕强,肖学珊,郭莉,张清炯.中国人Leber遗传性视神经病变的原发突变及临床特征.中华医学遗传学杂志,2005,22(3):334–336.
[3]Qu J,Zhou X,Zhao F,Liu X,Zhang M,Sun YH,Liang M,Yuan M,Liu Q,Tong Y,Wei QP,Yang L,Guan MX.Low penetrance of Leber's hereditary optic neuropathy in ten Han Chinese families carrying the ND6 T11484C mutation.Biochim Biophys Acta,2010,1800(3):305–312.
[4]Wallace DC,Singh G,Lott MT,Hodge JA,Schurr TG,Lezza AM,Elsas LJ 2nd,Nikoskelainen EK.Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy.Science,1988,242(4884):1427–1430.
[5]MITOMAP:A Human Mitochondrial Genome Database.http://www.mitomap.org,2009.
[6]Zhang M,Zhou X,Li C,Zhao F,Zhang J,Yuan M,Sun YH,Wang J,Tong Y,Liang M,Yang L,Cai W,Wang L,Qu J,Guan MX.Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4G11778A mutation.Mol Gene Metab,2010,101(2–3):192–199.
[7]Zhou X,Qian Y,Zhang J,Tong Y,Jiang P,Liang M,Dai X,Zhou H,Zhao F,Ji Y,Mo JQ,Qu J,Guan MX.Leber's hereditary optic neuropathy is associated with the T3866Cmutation in mitochondrial ND1 gene in three Han Chinese Families.Invest Ophthalmol Vis Sci,2012,53(8):4586–4594.
[8]Qu J,Li RH,Zhou XT,Tong Y,Lu F,Qian YP,Hu YW,Mo JQ,West CE,Guan MX.The novel A4435G mutation in the mitochondrial tRNAMet may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation.Invest Ophthalmol Vis Sci,2006,47(2):475–483.
[9]周晖晖,戴显宁,林蓓,米慧,刘晓玲,赵福新,张娟娟,周翔天,孙艳红,韦企平,瞿佳,管敏鑫.7例携带线粒体tRNAAla C5601T突变的Leber遗传性视神经病变家系的相关研究.遗传,2012,34(8):1031–1042.
[10]Qu J,Li R,Zhou X,Tong Y,Yang L,Chen J,Zhao F,Lu C,Qian Y,Lu F,Guan MX.Cosegregation of the ND4G11696A mutation with the LHON-associated ND4G11778A mutation in a four generation Chinese family.Mitochondrion,2007,7(1–2):140–146.
[11]冀延春,刘晓玲,赵福新,张娟娟,章豫,周翔天,瞿佳,管敏鑫.线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点.遗传,2011,33(4):322–328.
[12]Zhang JJ,Zhou XT,Zhou J,Li CW,Zhao FX,Wang Y,Meng YZ,Wang JY,Yuan MX,Cai WS,Tong Y,Sun YH,Yang L,Qu J,Guan MX.Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHONassociated G11778A mutation in four Chinese families.Biochem Biophys Res Commun,2010,399(4):647–653.
[13]Tong Y,Mao Y,Zhou X,Yang L,Zhang J,Cai W,Zhao F,Wang X,Lu F,Qu J,Guan MX.The mitochondrial tRNAGlu A14693G mutation may influence the phenotypic manifestation of ND1 G3460A mutation in a Chinese family with Leber’s hereditary optic neuropathy.Biochem Biophys Res Commun,2007,357(2):524–530.
[14]张永梅,冀延春,刘晓玲,周翔天,赵福新,孙艳红,韦企平,张娟娟,刘燕,瞿佳,管敏鑫.线粒体tRNAGluA14693G可能是与Leber遗传性视神经病变相关的基因突变.遗传,2010,32(4):353–359.
[15]Li RH,Qu J,Zhou XT,Tong Y,Hu YW,Qian YP,Lu F,Mo JQ,West CE,Guan MX.The mitochondrial tRNAThrA15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family.Gene,2006,376(1):79–86.
[16]Newman N J.Leber hereditary optic neuropathy:bad habits,bad vision.Brain,2009,132(Pt 9):2306–2308.
[17]Kirkman MA,Yu-Wai-Man P,Korsten A,Leonhardt M,Dimitriadis K,De Coo IF,Klopstock T,Chinnery PF.Gene environment interactions in Leber hereditary optic neuropathy.Brain,2009,132(Pt 9):2317–2326.
[18]Charlmers RM,Harding AE.A case-control study of Leber’s hereditary optic neuropathy.Brain,1996,119(Pt 5):1481–1486.
[19]Hudson G,Carelli V,Spruijt L,Gerards M,Mowbray C,Achilli A,Pyle A,Elson J,Howell N,La Morgia C,Valentino ML,Huoponen K,Savontaus ML,Nikoskelainen E,Sadun AA,Salomao SR,Belfort R Jr,Griffiths P,Man PY,de Coo RF,Horvath R,Zeviani M,Smeets HJ,Torroni A,Chinnery PF.Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.Am J Hum Genet,2007,81(2):228–233.
[20]Ji Y,Zhang AM,Jia X,Zhang YP,Xiao X,Li S,Guo X,Bandelt HJ,Zhang Q,Yao YG.Mitochondrial DNA haplogroups M7b1’2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese familieswith the m.11778G-->A mutation.Am J Hum Genet,2008,83(6):760–768.
[21]Brown MD,Torroni A,Reckord CL,Wallace DC.Phy-logenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent oc-currences of the common mutations.Hum Mutat,1995,6(4):311–325.
[22]Rieder MJ,Taylor SL,Tobe VO,Nickerson DA.Automating the identification of DNA variations using quality-based fluorescence re-sequencing:analysis of the human mitochondrial genome.Nucleic Acids Res,1998,26(4):967–973.
[23]Andrews RM,Kubacka I,Chinnery PF,Lightowlers RN,Turnbull DM,Howell N.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet,1999,23(2):147.
[24]Tanaka M,Cabrera VM,González AM,Larruga JM,Takeyasu T,Fuku N,Guo LJ,Hirose R,Fujita Y,Kurata M,Shinoda K,Umetsu K,Yamada Y,Oshida Y,Sato Y,Hattori N,Mizuno Y,Arai Y,Hirose N,Ohta S,Ogawa O,Tanaka Y,Kawamori R,Shamoto-Nagai M,Maruyama W,Shimokata H,Suzuki R,Shimodaira H.Mitochondrial genome variation in eastern Asia and the peopling of Japan.Genome Res,2004,14(10A):1832–1850.
[25]Kong QP,Bandelt HJ,Sun C,Yao YG,Salas A,Achilli A,Wang CY,Zhong L,Zhu CL,Wu SF,Torroni A,Zhang YP.Updating the East Asian mtDNA phylogeny:a prerequisite for the identification of pathogenic mutations.Hum Mol Genet,2006,15(13):2076–2086.
[26]Kaewsutthi S,Phasukkijwatana N,Joyjinda Y,Chuenkongkaew W,Kunhapan B,Tun AW,Suktitipat B,Lertrit P.Mitochondrial haplogroup background may influenceSoutheast Asian G11778A Leber hereditary optic neuropathy.Invest Ophthalmol Vis Sci,2011,52(7):4742–4748.
[27]Phasukkijwatana N,Kunhapan B,Stankovich J,Chuenkongkaew WL,Thomson R,Thornton T,Bahlo M,Mushiroda T,Nakamura Y,Mahasirimongkol S,Tun AW,Srisawat C,Limwongse C,Peerapittayamongkol C,Sura T,Suthammarak W,Lertrit P.Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand.Hum Genet,2010,128(1):39–49.
[28]Zhang AM,Jia X,Zhang QJ,Yao YG.No association between the SNPs(rs3749446 and rs1402000)in the PARL gene and LHON in Chinese patients with m.11778G>A.Hum Genet,2010,128(4):465–468.
[29]Ji Y,Jia X,Li S,Xiao X,Guo X,Zhang Q.Evaluation of the X-linked modifier loci for Leber hereditary optic neuropathy with the G11778A mutation in Chinese.Mol Vis,2010,16(47):416–424.