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