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he clinical and genetic analysis of Leber hereditary optic neuropathy with mitochondrial ND1 gene 3497C>T mutation |
LIANG Min1,2, HOU Lingling1, JIANG Feng1, GUAN Minxin2 |
1.Department of Clinical Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015; 2.Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical University, Wenzhou, 325035 |
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Cite this article: |
LIANG Min,HOU Lingling,JIANG Feng, et al. he clinical and genetic analysis of Leber hereditary optic neuropathy with mitochondrial ND1 gene 3497C>T mutation[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2018, 48(12): 859-863.
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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.
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Received: 06 August 2018
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[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. |
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