Mitochondrial variants may influence the phenotypic manifestation of Leber's hereditary optic neuropathy-associated ND4 G11778A mutation

Wanshi Cai^{a, b, #},
Qun Fu^{c, #},
Xiangtian Zhou^b,
Jia Qu^b,
Yi Tong^{a, d},
Min-Xin Guan^{a, b, e
, ,}

a.
Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China
b.
School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325003, China
c.
The Third Affiliated Hospital, Xinxiang Medical College, Xinxiang 453003, China
d.
The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
e.
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA

More Information

Corresponding author: E-mail address: gminxin88@gmail.com (Min-Xin Guan)

These authors contributed equally to this work.

摘要

- /
- /
- /
- /
- /
- /
Abstract: We report here the characterization of a five-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). Strikingly, this Chinese family displayed high penetrance and expressivity of visual loss. The average age-of-onset of vision loss was 18 years in this family. Nineteen (11 males/8 females) of 29 matrilineal relatives in this family developed visual loss with a wide range of severity, ranging from blindness to normal vision. Sequence analysis of mitochondrial genome in this pedigree revealed the presence of the ND4 G11778A mutation and 44 other variants belonging to Asian haplogroup M7b. The G11778A mutation is present at homoplasmy in matrilineal relatives of this Chinese family. Of other variants, the CO1 G6480A, ND5 T12811C and Cytb A15395G located at highly conserved residues of corresponding polypeptides. In fact, these variants were implicated to be involved in other clinical abnormalities. Here, these variants may act in synergy with the primary LHON-associated G11778A mutation. Thus, the mitochondrial dysfunction caused by the primary ND4 G11778A mutation may be worsened by these mitochondrial variants. The results imply that the G6480A, T12811C and A15395G variants might have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.
- Leber's hereditary optic neuropathy /
- mitochondrial DNA /
- mutation /
- haplotype /
- vision loss /
- modifier /
- Chinese
These authors contributed equally to this work.
注释:

HTML全文

参考文献(26)

[1]	Anderson, S., Bankier, A.T., Barrell, B.G. et al. Sequence and organization of the human mitochondrial genome Nature, 290 (1981),pp. 457-465
[2]	Bibb, M.J., van Etten, R.A., Wright, C.T. et al. Sequence and gene organization of mouse mitochondrial DNA Cell, 26 (1981),pp. 167-180
[3]	Brandon, M.C., Lott, M.T., Nguyen, K.C. et al. MITOMAP: A human mitochondrial genome database–2004 update Nucleic Acids Res., 33 (2005),pp. D611-D613
[4]	Brown, M.D., Torroni, A., Reckord, C.L. et al. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations Hum. Mutat., 6 (1995),pp. 311-325
[5]	Gadaleta, G., Pepe, G., De Candia, G. et al. J. Mol. Evol., 28 (1989),pp. 497-516
[6]	Guan, M.X., Enriquez, J.A., Fischel-Ghodsian, N. et al. Mol. Cell. Biol., 18 (1998),pp. 5868-5879
[7]	Huoponen, K., Lamminen, T., Juvonen, V. et al. The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy Hum. Genet., 92 (1993),pp. 379-384
[8]	Johns, D.R., Berman, J. Alternative, simultaneous complex I mitochondrial DNA mutations in Leber's hereditary optic neuropathy Biochem. Biophys. Res. Commun., 174 (1991),pp. 1324-1330
[9]	Kong, Q.P., Bandelt, H.J., Sun, C. et al. Updating the East Asian mtDNA phylogeny: A prerequisite for the identification of pathogenic mutations Hum. Mol. Genet., 15 (2006),pp. 2076-2086
[10]	Li, R., Qu, J., Zhou, X. et al. Gene, 376 (2006),pp. 79-86
[11]	Liu, V.W., Shi, H.H., Cheung, A.N. et al. High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas Cancer Res., 61 (2001),pp. 5998-6001
[12]	Mackey, D.A., Oostra, R.J., Rosenberg, T. et al. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy Am. J. Hum. Genet., 59 (1996),pp. 481-485
[13]	Man, P.Y., Griffiths, P.G., Brown, D.T. et al. The epidemiology of Leber hereditary optic neuropathy in the North East of England Am. J. Hum. Genet., 72 (2003),pp. 333-339
[14]	Mashima, Y., Yamada, K., Wakakura, M. et al. Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japanese families with Leber's hereditary optic neuropathy Curr. Eye Res., 17 (1998),pp. 403-408
[15]	Newman, N.J., Lott, M.T., Wallace, D.C. The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation Am. J. Ophthalmol., 111 (1991),pp. 750-762
[16]	Petros, J.A., Baumann, A.K., Ruiz-Pesini, E. et al. mtDNA mutations increase tumorigenicity in prostate cancer Proc. Natl. Acad. Sci. USA, 102 (2005),pp. 719-724
[17]	Qian, Y., Zhou, X., Hu, Y. et al. Clinical evaluation and mitochondrial DNA sequence analysis in three Chinese families with Leber's hereditary optic neuropathy Biochem. Biophys. Res. Commun., 332 (2005),pp. 614-621
[18]	Qu, J., Li, R., Tong, Y. et al. Only male matrilineal relatives with Leber's hereditary optic neuropathy in a large Chinese family carrying the mitochondrial DNA G11778A mutation Biochem. Biophys. Res. Commun., 328 (2005),pp. 1139-1145
[19]	Qu, J., Li, R., Zhou, X. et al. Invest. Ophthalmol. Vis. Sci., 47 (2006),pp. 475-483
[20]	Qu, J., Guan, M.X. Molecular pathogenetic mechanism of Leber's hereditary optic neuropathy Chinese J. Optometry Ophthalmol., 8 (2006),pp. 341-348
[21]	Qu, J., Li, R., Zhou, X. et al. Mitochondrion, 7 (2007),pp. 140-146
[22]	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 Nucleic Acids Res., 26 (1998),pp. 967-973
[23]	Roe, B.A., Ma, D.P., Wilson, R.K. et al. J. Biol. Chem., 260 (1985),pp. 9759-9774
[24]	Torroni, A., Petrozzi, M., D'Urbano, L. 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 (1997),pp. 1107-1121
[25]	Wallace, D.C., Singh, G., Lott, M.T. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy Science, 242 (1988),pp. 1427-1430
[26]	Yuan, H., Qian, Y., Xu, Y. et al. Am. J. Med. Genet. A, 138A (2005),pp. 133-140