, Volume 11, Issue 3, pp 349–356 | Cite as

Molecular characterization of six Chinese families with m.3460G>A and Leber hereditary optic neuropathy

  • Dandan Yu
  • Xiaoyun Jia
  • A-Mei Zhang
  • Xiangming Guo
  • Ya-Ping Zhang
  • Qingjiong Zhang
  • Yong-Gang Yao


The primary mutation m.3460G>A occurs with a very low frequency (∼1%) in Chinese patients with Leber hereditary optic neuropathy (LHON). Up to now, there is no comprehensive study of Chinese patients harboring this mutation. We characterized six unrelated probands with m.3460G>A in this study, which were identified from 1,626 patients with LHON or suspected with LHON. The overall penetrance of LHON (25.6% [10/39]) in four pedigrees with m.3460G>A was substantially lower than those families with m.11778G>A (33.3% [619/1859]) as reported in our previous study. Intriguingly, family Le688 with a heteroplasmic m.3460G>A presented a lower penetrance (12.5%) than the other three families with a homoplasmic mutation. There is an elevated gender bias (affected male to affected female = 4:1) in the four families with m.3460G>A compared to those LHON families with m.11778G>A (2.4:1). Complete mtDNA sequencing indicated that the six matrilines belonged to haplogroups B4d1, F2, A5b, M12a, D4b2b, and D4b2, respectively. We did not identify any potential secondary mutation(s) that will affect or be associated with the penetrance of LHON in the six probands by using an evolutionary analysis and protein secondary-structure prediction. Taken together, our results suggested that the m.3460G>A mutation occurred multiple times in Chinese LHON patients. The heteroplasmic status of mutation m.3460G>A might influence the penetrance of LHON in family Le688.


LHON m.3460G>A Chinese Phylogenetic analysis Multiple origins 



We thank patients for participating in this study. We are grateful to the members in Yao’s laboratory for helpful discussions. This study was supported by Yunnan Province (云南省高端人才计划2009CI119), Guangdong Province (广东省中国科学院全面战略合作项目2009B091300150), Chinese Academy of Sciences, and the National Science Fund for Distinguished Young Scholars (30925021).

Supplementary material

10048_2010_236_MOESM1_ESM.doc (30 kb)
Fig. S1 Evolutionary conservation analysis of the amino acid change caused by the previously unreported non-synonymous variant m.9423C>T in family Le1027. The amino acid sequences are compared to that derived from the human reference sequence [Homo sapiens (rCRS), GenBank accession number J01415] and nine different vertebrate species from GenBank: gorilla (Gorilla gorilla, NC_001645), mouse (Mus musculus, AY466499), cattle (Bos taurus, AY526085), horse (Equus caballus, EF597513), wolf (Canis lupus chanco, EU442884), dog (Canis familiaris, DQ480502), blue whale (Balaenoptera musculu, NC_001601), frog (Rana nigromaculata, AB043889), and zebrafish (Danio rerio, NC_002333) (DOC 30.5 kb)
10048_2010_236_MOESM2_ESM.doc (64 kb)
Fig. S2 A hydrophilicity chart for the MT-CO3 protein predicted by the TMpred program. The hydrophilicity of the MT-CO3 protein harboring the specific amino acid change caused by m.9423C>T was compared to the wild-type protein (rCRS) (DOC 64 kb)


  1. 1.
    Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ 2nd, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427–1430CrossRefPubMedGoogle Scholar
  2. 2.
    Harding AE, Sweeney MG, Govan GG, Riordan-Eva P (1995) Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation. Am J Hum Genet 57:77–86PubMedGoogle Scholar
  3. 3.
    Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE (1995) The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation. Brain 118:319–337CrossRefPubMedGoogle Scholar
  4. 4.
    Carelli V, Ross-Cisneros FN, Sadun AA (2004) Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res 23:53–89CrossRefPubMedGoogle Scholar
  5. 5.
    Man PYW, Turnbull DM, Chinnery PF (2002) Leber hereditary optic neuropathy. J Med Genet 39:162–169CrossRefPubMedGoogle Scholar
  6. 6.
    Yen M-Y, Wang A-G, Wei Y-H (2006) Leber's hereditary optic neuropathy: a multifactorial disease. Prog Retin Eye Res 25:381–396CrossRefPubMedGoogle Scholar
  7. 7.
    Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF (2009) Inherited mitochondrial optic neuropathies. J Med Genet 46:145–158CrossRefPubMedGoogle Scholar
  8. 8.
    Huoponen K, Vilkki J, Aula P, Nikoskelainen EK, Savontaus M-L (1991) A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. Am J Hum Genet 48:1147–1153PubMedGoogle Scholar
  9. 9.
    Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, Turnbull DM (1991) Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet 49:939–950PubMedGoogle Scholar
  10. 10.
    Mackey D, Howell N (1992) A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Am J Hum Genet 51:1218–1228PubMedGoogle Scholar
  11. 11.
    Hudson G, Carelli V, Spruijt L, Gerards M, Mowbray C, Achilli A, Pyle A, Elson J, Howell N, La Morgia C, Valentino ML, Huoponen K, Savontaus M-L, Nikoskelainen E, Sadun AA, Salomao SR, Belfort R Jr, Griffiths P, Man PY, de Coo RF, Horvath R, Zeviani M, Smeets HJ, Torroni A, Chinnery PF (2007) Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am J Hum Genet 81:228–233CrossRefPubMedGoogle Scholar
  12. 12.
    Jia X, Li S, Xiao X, Guo X, Zhang Q (2006) Molecular epidemiology of mtDNA mutations in 903 Chinese families suspected with Leber hereditary optic neuropathy. J Hum Genet 51:851–856CrossRefPubMedGoogle Scholar
  13. 13.
    Ji Y, Zhang A-M, Jia X, Zhang Y-P, Xiao X, Li S, Guo X, Bandelt H-J, Zhang Q, Yao Y-G (2008) 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 83:760–768CrossRefPubMedGoogle Scholar
  14. 14.
    Hudson G, Carelli V, Horvath R, Zeviani M, Smeets HJ, Chinnery PF (2007) X-Inactivation patterns in females harboring mtDNA mutations that cause Leber hereditary optic neuropathy. Mol Vis 13:2339–2343PubMedGoogle Scholar
  15. 15.
    Kirkman MA, Yu-Wai-Man P, Korsten A, Leonhardt M, Dimitriadis K, De Coo IF, Klopstock T, Chinnery PF (2009) Gene-environment interactions in Leber hereditary optic neuropathy. Brain 132:2317–2326CrossRefPubMedGoogle Scholar
  16. 16.
    Zhang A-M, Zou Y, Guo X, Jia X, Zhang Q, Yao Y-G (2009) Mitochondrial DNA mutation m.3635G>A may be associated with Leber hereditary optic neuropathy in Chinese. Biochem Biophys Res Commun 386:392–395CrossRefPubMedGoogle Scholar
  17. 17.
    Zhang A-M, Jia X, Yao Y-G, Zhang Q (2008) Co-occurrence of A1555G and G11778A in a Chinese family with high penetrance of Leber's hereditary optic neuropathy. Biochem Biophys Res Commun 376:221–224CrossRefPubMedGoogle Scholar
  18. 18.
    Ji Y, Jia X, Zhang Q, Yao Y-G (2007) mtDNA haplogroup distribution in Chinese patients with Leber's hereditary optic neuropathy and G11778A mutation. Biochem Biophys Res Commun 364:238–242CrossRefPubMedGoogle Scholar
  19. 19.
    Wang H-W, Jia X, Ji Y, Kong Q-P, Zhang Q, Yao Y-G, Zhang Y-P (2008) Strikingly different penetrance of LHON in two Chinese families with primary mutation G11778A is independent of mtDNA haplogroup background and secondary mutation G13708A. Mutat Res 643:48–53PubMedGoogle Scholar
  20. 20.
    Kong Q-P, Yao Y-G, Sun C, Bandelt H-J, Zhu C-L, Zhang Y-P (2003) Phylogeny of east Asian mitochondrial DNA lineages inferred from complete sequences. Am J Hum Genet 73:671–676CrossRefPubMedGoogle Scholar
  21. 21.
    Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147CrossRefPubMedGoogle Scholar
  22. 22.
    Kong Q-P, Bandelt H-J, Sun C, Yao Y-G, Salas A, Achilli A, Wang C-Y, Zhong L, Zhu C-L, Wu S-F, Torroni A, Zhang Y-P (2006) Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum Mol Genet 15:2076–2086CrossRefPubMedGoogle Scholar
  23. 23.
    van Oven M, Kayser M (2009) Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat 30:E386–394CrossRefPubMedGoogle Scholar
  24. 24.
    Bandelt H-J, Salas A, Taylor RW, Yao Y-G (2009) Exaggerated status of “novel” and “pathogenic” mtDNA sequence variants due to inadequate database searches. Hum Mutat 30:191–196CrossRefPubMedGoogle Scholar
  25. 25.
    Soares P, Ermini L, Thomson N, Mormina M, Rito T, Röhl A, Salas A, Oppenheimer S, Macaulay V, Richards MB (2009) Correcting for purifying selection: an improved human mitochondrial molecular clock. Am J Hum Genet 84:740–759CrossRefPubMedGoogle Scholar
  26. 26.
    De Vries DD, Went LN, Bruyn GW, Scholte HR, Hofstra RM, Bolhuis PA, van Oost BA (1996) Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. Am J Hum Genet 58:703–711PubMedGoogle Scholar
  27. 27.
    Bandelt H-J, Yao Y-G, Salas A, Kivisild T, Bravi CM (2007) High penetrance of sequencing errors and interpretative shortcomings in mtDNA sequence analysis of LHON patients. Biochem Biophys Res Commun 352:283–291CrossRefPubMedGoogle Scholar
  28. 28.
    Tanaka M, Cabrera VM, González AM, Larruga JM, Takeyasu T, Fuku N, Guo LJ, Hirose R, Fujita Y, Kurata M, Shinoda K, Umetsu K, Yamada Y, Oshida Y, Sato Y, Hattori N, Mizuno Y, Arai Y, Hirose N, Ohta S, Ogawa O, Tanaka Y, Kawamori R, Shamoto-Nagai M, Maruyama W, Shimokata H, Suzuki R, Shimodaira H (2004) Mitochondrial genome variation in eastern Asia and the peopling of Japan. Genome Res 14:1832–1850CrossRefPubMedGoogle Scholar
  29. 29.
    Jacobi FK, Leo-Kottler B, Mittelviefhaus K, Zrenner E, Meyer J, Pusch CM, Wissinger B (2001) Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy. Invest Ophthalmol Vis Sci 42:1208–1214PubMedGoogle Scholar
  30. 30.
    Kaplanová V, Zeman J, Hansíková H, Černá L, Houšt'ková H, Mišovicová N, Houštĕk J (2004) Segregation pattern and biochemical effect of the G3460A mtDNA mutation in 27 members of LHON family. J Neurol Sci 223:149–155CrossRefPubMedGoogle Scholar
  31. 31.
    Holt IJ, Miller DH, Harding AE (1989) Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy. J Med Genet 26:739–743CrossRefPubMedGoogle Scholar
  32. 32.
    Chinnery PF, Andrews RM, Turnbull DM, Howell N (2001) Leber hereditary optic neuropathy: does heteroplasmy influence the inheritance and expression of the G11778A mitochondrial DNA mutation? Am J Med Genet 98:235–243CrossRefPubMedGoogle Scholar
  33. 33.
    Black GCM, Morten K, Laborde A, Poulton J (1996) Leber's hereditary optic neuropathy: heteroplasmy is likely to be significant in the expression of LHON in families with the 3460 ND1 mutation. Br J Ophthalmol 80:915–917CrossRefPubMedGoogle Scholar
  34. 34.
    Torroni A, Cruciani F, Rengo C, Sellitto D, López-Bigas N, Rabionet R, Govea N, López De Munain A, Sarduy M, Romero L, Villamar M, del Castillo I, Moreno F, Estivill X, Scozzari R (1999) The A1555G mutation in the 12S rRNA gene of human mtDNA: recurrent origins and founder events in families affected by sensorineural deafness. Am J Hum Genet 65:1349–1358CrossRefPubMedGoogle Scholar
  35. 35.
    Torroni A, Campos Y, Rengo C, Sellitto D, Achilli A, Magri C, Semino O, García A, Jara P, Arenas J, Scozzari R (2003) Mitochondrial DNA haplogroups do not play a role in the variable phenotypic presentation of the A3243G mutation. Am J Hum Genet 72:1005–1012CrossRefPubMedGoogle Scholar
  36. 36.
    Yao Y-G, Salas A, Bravi CM, Bandelt H-J (2006) A reappraisal of complete mtDNA variation in East Asian families with hearing impairment. Hum Genet 119:505–515CrossRefPubMedGoogle Scholar
  37. 37.
    Torroni A, Petrozzi M, D'Urbano L, Sellitto D, Zeviani M, Carrara F, Carducci C, Leuzzi V, Carelli V, Barboni P, De Negri A, Scozzari R (1997) 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 60:1107–1121PubMedGoogle Scholar
  38. 38.
    Man PYW, Howell N, Mackey DA, Nørby S, Rosenberg T, Turnbull DM, Chinnery PF (2004) Mitochondrial DNA haplogroup distribution within Leber hereditary optic neuropathy pedigrees. J Med Genet 41:e41CrossRefPubMedGoogle Scholar
  39. 39.
    Brown MD, Sun F, Wallace DC (1997) Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage. Am J Hum Genet 60:381–387CrossRefPubMedGoogle Scholar
  40. 40.
    Liu VWS, Shi HH, Cheung ANY, Chiu PM, Leung TW, Nagley P, Wong LC, Ngan HYS (2001) High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas. Cancer Res 61:5998–6001PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Dandan Yu
    • 1
  • Xiaoyun Jia
    • 2
  • A-Mei Zhang
    • 1
    • 4
  • Xiangming Guo
    • 2
  • Ya-Ping Zhang
    • 3
  • Qingjiong Zhang
    • 2
  • Yong-Gang Yao
    • 1
  1. 1.Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan ProvinceKunming Institute of ZoologyKunmingChina
  2. 2.State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhouChina
  3. 3.State Key Laboratory of Genetic Resource and EvolutionKunming Institute of Zoology, Chinese Academy of SciencesKunmingChina
  4. 4.Graduate School of the Chinese Academy of SciencesBeijingChina

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