仅女性发病的Leber遗传性视神经病变家系的表型分析

Abstract
Figure/Table
References (0)
Related Citation (15)

Download: PDF (1477 KB) HTML (1 KB)
Export: BibTeX | EndNote (RIS)

Abstract Objective: Phenotypic performance of 11 Leber’s hereditary optic neuropathy (LHON) pedigrees carrying m.11778G>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.11778G>A mutation. Results: Screening revealed that 11 cases of LHON pedigrees carrying m.11778G>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 B5a, Z, N9, B4c1b, G2h, B5a, M7b, N9a10, C7b, M7b1, 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.11778G>A mutation and different maternal members in the same mitochondrial genetic background. This suggests that m.11778G>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.

Key words： Leber’s hereditary optic neuropathy maternal inheritance mitochondria penetrance mitochon-drial haplotype

Received: 19 February 2019

	Service
	E-mail this article
	Add to my bookshelf
	Add to citation manager
	E-mail Alert
	RSS
	Articles by authors
	LYU Yuanyuan
	XU Man
	ZHANG Juanjuan
	GUAN Minxin

URL:

https://xb.wmu.edu.cn/EN/ OR https://xb.wmu.edu.cn/EN/Y2019/V49/I7/475

[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.
[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 J Hum 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 J Hum Genet, 2007, 81(2): 228-233.
[21] TORRINI A, PETROZZI M, D’URBANO L, et al. Tropean-specific 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 J Hum 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 G11778A mutation 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.