Objective To report the clinical, genetic, and molecular characterizations of three Chinese families with Leber′s hereditary optic neuropathy (LHON). Methods Experimental study. Three Chinese Han families were identified with LHON. Ophthalmologic examinations were conducted on the probands and other matrilineal relatives of these families. Meanwhile, entire mitochondrial DNA (mtDNA) of three probands were amplified by PCR using 24 pairs of oligonucleotice primers with overlapping fragments. Results The probands had mild visual impairment. Strikingly, there was extremely low penetrance of visual impairment in these Chinese families, with a penetrance of 11.1%, 10.0% and 4.0%. Molecular analysis of mitochondrial DNA in these pedigrees revealed the absence of three common LHON associated with ND1 G3460A, ND4 G11778A, and ND6 T14484C mutations but there was a presence of homoplastic LHON associated with the ND6 T14502C (I58V) mutation in probands and other matrilineal relatives. These mtDNA polymorphism sites belong to the Asian haplogroups M10a. The T14502C mutation in the ND6 gene, which is the substitution of a highly conserved isoleucine for valine (I58V) at the amino acid position 58, had changed the structure and influenced the function of protein, causing visual impairment. Conclusion The results suggest that the ND6 T14502C mutation might be involved in the pathogenesis of Leber′s hereditary optic neuropathy in the three Chinese Han families studied.
林蓓,米慧,孟祥娟,朱金萍,张娟娟,刘晓玲,孙艳红,周翔天,瞿佳,管敏鑫. Leber遗传性视神经病变线粒体ND6 T14502C突变的三个汉族家系[J]. 中华眼视光学与视觉科学杂志, 2013, 15(9): 537-542.
LIN Bei,MI Hui,MENG Xiang-Juan,ZHU Jin-ping,ZHANG Juan-juan,LIU Xiao-ling,SUN Yan-hong,ZHOU Xiang-tian,OU Jia,GUAN Min-xin. Leber′s hereditary optic neuropathy is associated with the T14502C mutation in mitochondrial ND6 gene in three Han Chinese families. Chinese Journal of Optometry Ophthalmology and Visual Science, 2013, 15(9): 537-542. DOI: 10.3760/cma.j.issn.1674-845X.2013.09.007
Yu-Wai-Man P, Griffiths PG, Hudson G, et al. Inherited mitochondrial optic neuropathies. J Med Genet,2009,46:145-158.
[2]
Carelli V, La Morgia C, Valentino ML, et al. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim Biophys Acta,2009,1787:518-528.
[3]
Wallace DC, Singh G, Lott MT,et al. Mitochondrial DNA mutation associated with Leber′s hereditary optic neuropathy. Science,1988,242:1427-1430.
[4]
MTOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org,2009.
[5]
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. Mol Genet Metab,2010,101:192-199.
[6]
Zhou X, Qian Y, Zhang J, et al. Leber′s Hereditary Optic Neuropathy Is Associated with the T3866C Mutation in Mitochondrial ND1 Gene in Three Han Chinese Families. Invest Ophthalmol Vis Sci,2012,53:4586-4594.
[7]
Qu J, Li R, Zhou X, et al. The Novel A4435G Mutation in the Mitochondrial tRNAMet May Modulate the Phenotypic Expression of the LHON-Associated ND4 G11778A Mutation. Invest Ophthalmol Vis Sci,2006,47:475-483.
Liu XL, Zhou X, Zhou J, et al. Leber′s Hereditary Optic Neuropathy Is Associated with the T12338C Mutation in Mitochondrial ND5 Gene in Six Han Chinese Families. Ophthalmology,2011,118: 978-985.
Kong QP, Bandelt HJ, Sun C, et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum Mol Genet,2006,15:2076-2086.
[13]
Ingman M, Gyllensten U. mtDB: Human Mitochondrial Genome Database, a resource for population genetics and medical sciences. Nucleic Acids Res,2006,34:D749-751.
[14]
Sun YH, Wei QP, Zhou X, et al. Leber′s hereditary optic neuropathy is associated with the mitochondrial ND6 T14484C mutation in three Chinese families. Biochem Biophys Res Commun,2006,347:221-225.
[15]
Qian Y, Zhou X, Liang M, et al. The altered activity of complex III may contribute to the high penetrance of Leber's hereditary optic neuropathy in a Chinese family carrying the ND4 G11778A mutation. Mitochondrion,2011,11:871-877.
[16]
Zhang J, Zhou X, Zhou J, et al. Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHON-associated G11778A mutation in four Chinese families. Biochem Biophys Res Commun,2010,399:647-653.
[17]
Liang M, Guan M, Zhao F, et al. Leber′s hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation. Biochem Biophys Res Commun,2009,383:286-292.
[18]
Qu J, Zhou X, Zhang J, et al. Extremely Low Penetrance of Leber′s Hereditary Optic Neuropathy in 8 Han Chinese Families Carrying the ND4 G11778A Mutation. Ophthalmology,2009,116:558-564.
[19]
Zhang S, Wang L, Hao Y, et al. T14484C and T14502C in the mitochondrial ND6 gene are associated with Leber′s hereditary optic neuropathy in a Chinese family. Mitochondrion,2008,8:205-210.
[20]
Zhao F, Guan M, Zhou X, et al. Leber′s hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation. Biochem Biophys Res Commun,2009,389:466-472.
[21]
Ozawa T, Tanaka M, Sugiyama S, et al. Patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson′s disease and mitochondrial encephalomyopathy. Biochem Biophys Res Commun,1991,177: 518-525.