Abstract
To investigate the pathophysiology of Leber’s hereditary optic neuropathy (LHON), a cohort of 1164 Han Chinese subjects with LHON were screened for ND1 G3460A mutation. A total of 295 subjects from 16 Han Chinese families carrying the G3460A mutation underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The incidence of G3460A mutation was 1.4% in this cohort of Chinese subjects with LHON. Twenty-seven (20 males/7 females) of 109 matrilineal relatives among 10 Chinese pedigrees carrying this mutation exhibited a wide range of severity and age-at-onset in visual impairment. Penetrances of optic neuropathy ranged from 7.1% to 50%, with the average of 24.5%. The age-at-onset of 27 affected matrilineal relatives varied from 10 to 40 years, with the average of 22 years. Molecular analysis identified the homoplasmic G3460A mutation and distinct sets of variants belonging to eight haplogroups. Haplogroup M with G3460A mutation was of higher frequency than those in controls. The penetrances of visual loss in families carrying mitochondrial DNA haplogroups A, B and M were higher than those in other families. Furthermore, haplogroup-specific variants tRNASer(AGY) A12223G, tRNAThr G15927A and tRNAGlu A14693G may enhance the penetrance of visual loss in these families. The G3460A mutation occurred through recurrent origins and founder events in Chinese population. Mitochondrial modifiers may modulate the penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the G3460A mutation. Thus, our findings may provide new insights into the understanding of pathophysiology and valuable information on the management of LHON.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Accession codes
References
Newman, N. J. Leber’s hereditary optic neuropathy. New genetic considerations. Arch. Neurol. 50, 540–548 (1993).
Nikoskelainen, E. K. Clinical picture of lhon. Clin. Neurosci. 2, 115–120 (1994).
Man, P. Y., Griffiths, P. G., Brown, D. T., Howell, N., Turnbull, D. M. & Chinnery, P. F. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am. J. Hum. Genet. 72, 333–339 (2003).
Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).
Howell, N., Oostra, R. J., Bolhuis, P. A., Spruijt, L., Clarke, L. A., Mackey, D. A. et al. Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Am. J. Hum. Genet. 72, 1460–1469 (2003).
Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).
Brown, M. D., Torroni, A., Reckord, C. L. & Wallace, D. Phylogenetic analysis of Lebers hereditary optic neuropathy mitochondrial DNAs indicates multiple independent occurrences of the common mutations. Hum. Mutat. 6, 311–325 (1995).
Mackey, D. A., Oostra, R. J., Rosenberg, T., Nikoskelainen, E., Poulton, J., Barratt, T. et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am. J. Hum. Genet. 59, 481–485 (1996).
Mashima, Y., Yamada, K., Wakakura, M., Kigasawa, K., Kudoh, J., Shimizu, N. et al. Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber’s hereditary optic neuropathy. Cur. Eye Res. 17, 403–408 (1998).
Carelli, V., La Morgia, C., Valentino, M. L., Barboni, P., Ross-Cisneros, F. N. & Sudan, A. A. Retinal ganglion cell neurodegeneration in mitochondrial inherited disorders. Biochim. Biophys. Acta 1787, 518–528 (2009).
Hofhaus, G., Johns, D. R., Hurko, O., Attardi, G. & Chomyn, A. Respiration and growth defects in transmitochondrial cell lines carrying the 11778 mutation associated with Leber's hereditary optic neuropathy. J. Biol. Chem. 271, 13155–13161 (1996).
Brown, M. D., Trounce, I. A., Jun, A. S., Attardi, G. & Chomyn, A. Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber's hereditary optic neuropathy mitochondrial DNA mutation. J. Biol. Chem. 275, 39831–39836 (2000).
Qian, Y., Zhou, X., Liang, M., Qu, J. & Guan, M. X. 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 11, 871–877 (2011).
Riordan-Eva, P., Sanders, M. D., Govan, G. G., Sweeney, M. G., Da Costa, J., Harding, A. E. et al. The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118 (Pt 2), 319–337 (1995).
Yu-Wai-Man, P., Griffiths, P. G., Hudson, G. & Chinnery, P. F. Inherited mitochondrial optic neuropathies. J. Med. Genet. 46, 145–158 (2009).
Yen, M. Y., Wang, A. G. & Wei, Y. H. Leber’s hereditary optic neuropathy: a multifactorial disease. Prog. Retin. Eye Res. 25, 381–396 (2006).
Hudson, G., Keers, S., Yu Wai Man, P., Griffiths, P., Huoponen, K., Savontaus, M. L. et al. Identification of an X-chromosomal locus and haplotype modulating the phenotype of a mitochondrial DNA disorder. Am. J. Hum. Genet. 77, 1086–1091 (2005).
Torroni, A., Petrozzi, M., Durbano, L., Sellitto, D., Zeviani, M., Carrara, F. et al. Haplotype and phylogenetic analyses suggest that one european-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. Am. J. Hum. Genet. 60, 1107–1121 (1997).
Qu, J., Li, R., Zhou, X., Tong, Y., Lu, F., Qian, Y. 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. 47, 475–483 (2006).
Ji, Y., Zhang, A. M., Jia, X., Zhang, Y. P., Xiao, X., Li, S. et al. Mitochondrial DNA haplogroups M7b1'2 and M8a affect clinical expression of Leber hereditary optic neuropathy in Chinese families with the m.11778G>A mutation. Am. J. Hum. Genet. 83, 760–768 (2008).
Brown, M. D., Starikovskaya, E., Derbeneva, O., Hosseini, S., Allen, J. C., Mikhailovskaya, I. E. et al. The role of mtdna background in disease expression: a new primary LHON mutation associated with Western Eurasian haplogroup J. Hum. Genet. 110, 130–138 (2002).
Hudson, G., Carelli, V., Spruijt, L., Gerards, M., Mowbray, C., Achilli, A. et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 81, 228–233 (2007).
Pello, R., Martin, M. A., Carelli, V., Nijtmans, L. G., Achilli, A., Pala, M. et al. Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum. Mol. Genet. 17, 4001–4011 (2008).
Kaewsutthi, S., Phasukkijwatana, N., Joyjinda, Y., Chuenkongkaew, W., Kunhapan, B. & Tun, A. W. Mitochondrial haplogroup background may influence Southeast Asian G11778A Leber hereditary optic neuropathy. Invest. Ophthalmol. Vis. Sci. 52, 4742–4748 (2011).
Li, R., Qu, J., Zhou, X., Tong, Y., Hu, Y., Qian, Y. et al. The mitochondrial tRNAThr A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family. Gene 376, 79–86 (2006).
Qu, J., Li, R., Zhou, X., Tong, Y., Yang, L., Chen, J. et al. Cosegregation of the ND4 G11778A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family. Mitochondrion 7, 140–146 (2007).
Zhang, J., Zhou, X., Zhou, J., Li, C., Zhao, F., Wang, Y. et al. Mitochondrial ND6 T14502C variant may modulate the phenotypic expression of LHON-associated G11778A mutation in four Chinese families. Biochem. Biophys. Res. Commun. 399, 647–653 (2010).
Zhang, M., Zhou, X., Li, C., Zhao, F., Zhang, J., Yuan, M. 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. 101, 192–199 (2010).
Rieder, M. J., Taylor, S. L., Tobe, V. O. & Nickerson, D. A. Automating the identification of DNA variations using quality-based fluorescence re-sequencing: analysis of the human mitochondrial genome. Nucleic Acids Res. 26, 967–973 (1998).
Andrews, R. M., Kubacka, I., Chinnery, P. F., Lightowlers, R. N., Turnbull, D. M., Howell, N. et al. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat. Genet. 23, 147 (1999).
Tanaka, M., Cabrera, V. M., Gonzalez, A. M., Larruga, J. M., Takeyasu, T., Fuku, N. et al. Mitochondrial genome variation in Eastern Asia and the peopling of Japan. Genome Res. 14, 1832–1850 (2004).
Kong, Q. P., Bandelt, H. J., Sun, C., Yao, Y. G., Salas, A., Achilli, A. et al. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum. Mol. Genet. 15, 2076–2086 (2006).
Tong, Y., Mao, Y., Zhou, X., Yang, L., Zhang, J., Cai, W. et al. 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. 357, 524–530 (2007).
Tong, Y., Sun, Y. H., Zhou, X., Zhao, F., Mao, Y., Wei, Q. P. et al. Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation. Mol. Genet. Metab. 99, 417–424 (2010).
Bibb, M. J., Van Etten, R. A., Wright, C. T., Walberg, M. W. & Clayton, D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell 26, 167–180 (1981).
Gadaleta, G., Pepe, G., De Candia, G., Quagliariello, C., Sbisà, E. & Saccone, C. The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome: cryptic signals revealed by comparative analysis between vertebrates. J. Mol. Evol. 28, 497–516 (1989).
Roe, B. A., Ma, D. P., Wilson, R. K. & Wong, J. F. The complete nucleotide sequence of the Xenopus laevis mitochondrial genome. J. Biol. Chem. 260, 9759–9774 (1985).
Huoponen, K., Vilkki, J., Aula, P., Nikoskelainen, E. K. & Savontaus, M. L. A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am. J. Hum. Genet. 48, 1147–1153 (1991).
Howell, N., Kubacka, I., Xu, M. & McCullough, D. A. Leber hereditary optic neuropathy - involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. Am. J. Hum. Genet. 48, 935–942 (1991).
Jia, X., Li, S., Xiao, X., Guo, X. & Zhang, Q. Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy. J. Hum. Genet. 51, 851–856 (2006).
Brown, M. D. & Wallace, D. C. Spectrum of mitochondrial-DNA mutations in Lebers hereditary optic neuropathy. Clin. Neurosci. 2, 138–145 (1994).
Macmillan, C., Kirkham, T., Fu, K., Allison, V., Andermann, E., Chitayat, D. et al. Pedigree analysis of French Canadian families with T14484C Leber's hereditary optic neuropathy. Neurology 50, 417–422 (1998).
Johns, D. R., Smith, K. H. & Miller, N. R. Leber's hereditary optic neuropathy. Clinical manifestations of the 3460 mutation. Arch. Ophthalmol. 110, 1577–1581 (1992).
Harding, A. E., Sweeney, M. G., Govan, G. G. & Riordan-Eva, P. Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtdna mutation. Am. J. Hum. Genet. 57, 77–86 (1995).
Johns, D. R., Heher, K. L., Miller, N. R. & Smith, K. H. Leber’s hereditary optic neuropathy. Clinical manifestations of the 14484 mutation. Arch. Ophthalmol. 111, 495–498 (1993).
Phasukkijwatana, N., Kunhapan, B., Stankovich, J., Chuenkongkaew, W. L., Thomson, R., Thornton, T. et al. Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand. Hum. Genet. 128, 39–49 (2010).
Kirkman, M. A., Yu-Wai-Man, P., Korsten, A., Leonhardt, M., Dimitriadis, K. & De Coo, I. F. Gene-environment interactions in Leber hereditary optic neuropathy. Brain 132, 2317–2326 (2009).
Johns, D. R. & Berman, J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 174, 1324–1330 (1991).
Suzuki, T., Nagao, A. & Suzuki, T. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu. Rev. Genet. 45, 299–329 (2011).
Lu, J., Li, Z., Zhu, Y., Yang, A., Li, R., Zheng, J. et al. Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mitochondrion 10, 380–390 (2010).
Acknowledgements
This work was supported by National Key Technologies R&D Program Grant 2012BAI09B03 from the Ministry of Science and Technology of China (M-XG and PJ) and a Chinese Young Scholar Award (81200724) from National Science Foundation of China (JZ) and a research award (Y201225490) from the Ministry of Education of Zhejiang Province (YJ).
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
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 Hum Genet 59, 134–140 (2014). https://doi.org/10.1038/jhg.2013.134
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2013.134
Keywords
This article is cited by
-
Haplogroup Context is Less Important in the Penetrance of Mitochondrial DNA Complex I Mutations Compared to mt-tRNA Mutations
Journal of Molecular Evolution (2018)
