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

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摘要目的：探讨携带线粒体ND1基因3497C＞T突变的Leber遗传性视神经病变（LHON）家系临床与遗传学特征。方法：对6个携带线粒体ND1基因3497C＞T突变的LHON家系进行家系调查，对先证者进行详细的眼科学检查及线粒体全基因组分析，利用转线粒体细胞系进行呼吸链复合物酶活力检测。结果：6个家系中每个家系都只有1人患病，其中男5例，女1例。患者眼底主要表现为视盘色淡，边界不清。光学相干断层扫描显示2例患者颞侧及鼻侧视网膜神经纤维层均有不同层度的变薄，4例患者无明显改变。携带线粒体3497C＞T突变的转线粒体细胞株其呼吸链复合物I酶活力为正常对照的87.6%。结论：LHON患者眼底存在不同程度病变，线粒体ND1基因3497C＞T突变是LHON家系发病的原因之一，该位点可作为LHON的筛查位点之一。

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关键词 ： Leber遗传性视神经病变, 线粒体DNA, 眼底检查, 光学相干断层扫描, 酶活力

Abstract：Objective: To investigate the clinical and molecular characteristics of six Leber hereditary optic neuropathy (LHON) families with mitochondrial ND1 gene 3497C>T mutation. Methods: Clinical data were collected from six pedigrees, and detailed ophthalmology examination and mitochondrial genomes were conducted for the six probands. Then we measured the activities of respiratory complexes using the cybrid cell models from six probands and two controls. Results: Only one person in each of the six families exhibited the variable severity and age-at-onset in visual dysfunction. The affected matrilineal relatives consisted of 5 males and 1 female. All patients had pale disc and unclear boundary. Optical coherence tomography (OCT) revealed that the thickness of retinal nerve fibers (RNFL) in two patients were significantly thinner in nasal and temporal quadrant, while the other patients had no differences in all quadrants. The activity of complex I in the mutant cell lines carrying 3497C>T mutation were 87.6% relative to control cell lines. However, the activities of complex II, III and IV in mutant cell lines were comparable to those of two control cell lines. Conclusion: LHOH patients exeist different levels of fundus lesions. Mitochondrial 3497C>T mutation plays an important role in the occurrence of LHON, and this site can be added to the list of inherited factors for LHON screening.

Key words： Leber’s hereditary optic neuropathy mitochondrial DNA fund examination optical coherence tomography enzyme activity

收稿日期: 2018-08-06

基金资助:国家自然科学基金青年基金资助项目（81600769）；温州医科大学附属第一医院青年英才计划（qnyc077）；温州医科大学附属第一医院博士科研启动基金（2015QD013）。

通讯作者: 管敏鑫，教授，Email：gminxin88@gmail.com。

作者简介: 梁敏（1983-），女，河南安阳人，讲师，博士。

链接本文:

https://xb.wmu.edu.cn/CN/ 或 https://xb.wmu.edu.cn/CN/Y2018/V48/I12/859

[1] WALLACE D C, SINGH G, LOTT M T, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy[J]. Science, 1988, 242(4884): 1427-1430.
[2] WALLACE D C, LOTT M T. Leber hereditary optic neuropathy: exemplar of an mtDNA disease[J]. Handb Exp Pharmacol, 2017, 240: 339-376.
[3] MAZUNIN I O, VOLODKO N V. Leber hereditary optic neuropathy[J]. Vestn Oftalmol, 2018, 134(2): 92-97.
[4] YU-WAI-MAN P, VOTRUBA M, BURTÉ F, et al. A neurodegenerative perspective on mitochondrial optic neuropa-thies[J]. Acta Neuropathol, 2016, 132(6): 789-806.
[5] PILZ Y L, BASS S J, SHERMAN J. A review of mitochondrial optic neuropathies: from inherited to acquired forms [J]. J Optom, 2017, 10(4): 205-214.
[6] YU-WAI-MAN P, GRIFFITHS P G, HUDSON G, et al. Inherited mitochondrial optic neuropathies[J]. J Med Genet, 2009, 46(3): 145-158.
[7] MEYERSON C, VAN STAVERN G, MCCLELLAND C. Leber hereditary optic neuropathy: current perspectives[J]. Clin Ophthalmol, 2015, 9: 1165-1176.
[8] JANCIC J, SAMARDZIC J, STOJANOVIC S, et al. Leber’s hereditary optic neuropathy: novel views and persisting challenges[J]. CNS Neurol Disord Drug Targets, 2017, 16(8): 927-935.
[9] CAPORALI L, MARESCA A, CAPRISTO M, et al. Incomplete penetrance in mitochondrial optic neuropathies[J]. Mitochondrion, 2017, 36: 130-137.
[10] ZHANG J, JI Y, LU Y, et al. Leber’s hereditary optic neuropathy (LHON)-associated ND5 12338T>C mutation altered the assembly and function of complex I, apoptosis and mitophagy[J]. Hum Mol Genet, 2018, 27(11): 1999-2011.
[11] JØRSTAD Ø K, ØDEGAARD E M, HEIMDAL K R, et al. Leber hereditary optic neuropathy caused by a mitochondrial DNA 10663T>C point mutation and its response to idebenone treatment[J]. J Neuroophthalmol, 2018, 38(1): 129-131.
[12] JI Y, QIAO L, LIANG X, et al. Leber’s hereditary optic neuropathy is potentially associated with a novel m.5587T>C mutation in two pedigrees[J]. Mol Med Rep, 2017, 16(6): 8997-9004.
[13] ZHANG J, JIANG P, JIN X, et al. Leber’s hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families[J]. Mitochondrion, 2014, 18: 18-26.
[14] KING M P, ATTARDI G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementa-tion[J]. Science, 1989, 246(4929): 500-503.
[15] RUIZ-PESINI E, LOTT M T, PROCACCIO V, et al. An enhanced MITOMAP with a global mtDNA mutational phy-logeny[J]. Nucleic Acids Res, 2007, 35: D823-828.
[16] JIANG P, LIANG M, ZHANG C, et al. Biochemical evidence for a mitochondrial genetic modifier in the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated mitochondrial DNA mutation[J]. Hum Mol Genet, 2016, 25(16): 3613-3625.
[17] JIANG P, LIANG M, ZHANG J, et al. Prevalence of mitochondrial ND4 mutations in 1281 Han Chinese subjects with Leber’s hereditary optic neuropathy[J]. Invest Ophthalmol Vis Sci, 2015, 56(8): 4778-4788.
[18] DAI Y, WANG C, NIE Z, et al. Mutation analysis of Leber’s hereditary optic neuropathy using a multi-gene panel[J].Biomed Rep, 2018, 8(1): 51-58.
[19] YU-WAI-MAN P, VOTRUBA M, BURTÉ F, et al. A neurodegenerative perspective on mitochondrial optic neuropa-thies[J]. Acta Neuropathol, 2016, 132(6): 789-806.
[20] MOSTER S J, MOSTER M L, SCANNELL BRYAN M,
et al. Retinal ganglion cell and inner plexiform layer loss correlate with visual acuity loss in LHON: a longitudinal, segmentation OCT analysis[J]. Invest Ophthalmol Vis Sci, 2016, 57(8): 3872-3883.
[21] MANFREADY R A, HEDGES T R 3RD, MENDOZA-SANTIESTEBAN C E. Structural and functional degeneration of retinal nerves in sibling carriers of a Leber’s hereditary optic neuropathy mutation[J]. Can J Ophthalmol, 2018, 53(1): e1-e4.
[22] BARBONI P, SAVINI G, FEUER W J, et al. Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers[J]. Eur J Ophthalmol, 2012, 22(6): 985-991.
[23] BALDUCCI N, SAVINI G, CASCAVILLA M L, et al. Macular nerve fibre and ganglion cell layer changes in acute Leber’s hereditary optic neuropathy[J]. Br J Ophthalmol, 2016, 100(9): 1232-1237.
[24] MAJANDER A, ROBSON A G, JOÃO C, et al. The pattern of retinal ganglion cell dysfunction in Leber hereditary optic neuropathy[J]. Mitochondrion, 2017, 36: 138-149.
[25] LIANG M, JIANG P, LI F, et al. Frequency and spectrum of mitochondrial ND6 mutations in 1218 Han Chinese subjects with Leber’s hereditary optic neuropathy[J]. Invest Ophthalmol Vis Sci, 2014, 55(3): 1321-1331.
[26] YING Z, ZHENG J, CAI Z, et al. Mitochondrial haplogroup B increases the risk for hearing loss among the Eastern Asian pedigrees carrying 12S rRNA 1555A>G mutation[J]. Protein Cell, 2015, 6(11): 844-848.
[27] LUO Y J, GAO W X, LI S Z, et al. Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese[J]. Genet Mol Res, 2012, 11(4): 3658-3667.
[28] XIE S, ZHANG J, SUN J, et al. Mitochondrial haplogroup D4j specific variant m.11696G>A(MT-ND4) may increase the penetrance and expressivity of the LHON-associated m.11778G>a mutation in Chinese pedigrees[J]. Mitochondrial DNA A DNA Mapp Seq Anal, 2017, 28(3): 434-441.
[29] ZHANG M, ZHOU X, LI C, et al. Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation[J]. Mol Genet Metab, 2010, 101(2-3): 192-199.
[30] JI Y, LIANG M, ZHANG J, et al. Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON-associated ND1 G3460A mutation in Chinese families[J]. J Hum Genet, 2014, 59(3): 134-140.