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Leber's Hereditary Optic Neuropathy (LHON) Disease Mutations

A. "Top 19" Primary LHON mutations, the first 3 mutations listed (in boldface) represent approximately 95% of all cases. The remaining mutations are listed in nucleotide order.

Mutation	NT Δ	AA Δ	AA Cons^a	% Patients	% Controls	Het.^b	Penetrance^c % Relatives	Penetrance^c % Males	% Recovery^d	References
m.11778G>A ND4	G-A	R340H	100%	69	0	+/-	33-60	82	4	( 27)
m.3460G>A ND1	G-A	A52T	91%	13	0	+/-	14-75	40-80	22	( 10, 16)
m.14484T>C ND6	T-C	M64V	31%	14	0	+/-	27-80	68	37-65	( 2, 13, 18)
m.3376G>A ND1	G-A	E24K	98%	Rare	0	+/+	NA	NA	NA	( 33, 34, 35)
m.3635G>A ND1	G-A	S110N	93%	Rare	0	+/-	29 (range 11-64)	54 (range 25-100)	Low	( 3)
m.3697G>A ND1	G-A	G131S	100%	Rare	0	+/+	NA	NA	NA	( 32)
m.3700G>A ND1	G-A	A112T	93%	Rare	0	-	NA	NA	UN	( 1a, 7)
m.3733G>A ND1	G-A	E143K	100%	Rare	0	+/-	24-30	36-44	Yes	( 1a, 26)
m.4171C>A ND1	C-A	L289M	93%	Rare	0	+/-	46	47	Yes	( 20)
m.10197G>A ND3	G-A	A47T	96%	Rare	4/42616	+/+	NA	NA	NA	( 36)
m.10663T>C ND4L	T-C	V65A	89%	Rare	0	+/-	56	60	UN	( 1a, 1b)
m.13051G>A ND5	G-A	G239S	98%	Rare	0	-	56	63	UN	( 5b, 14)
m.13094T>C ND5	T-C	V253A	100%	Rare	0	+	NA	NA	Yes	( 5c, 23b)
m.14459G>A ND6	G-A	A72V	89%	Rare	0	+	NA	NA	Low	( 8, 19, 24)
m.14482C>A ND6	C-A	M64I	31%	Rare	0	+/-	NA	89	Yes	( 1a, 25)
m.14482C>G ND6	C-G	M64I	31%	Rare	0	-	NA	NA	UN	( 11)
m.14495A>G ND6	A-G	L60S	100%	Rare	0	+	NA	NA	Low	( 4)
m.14502T>C ND6	T-C	I58V	78%	Rare	0	-	14502:10% 14502+11778:37%	14502:11% 14502+11778:47%	UN	( 1a, 30, 31)
m.14568C>T ND6	C-T	G36S	87%	Rare	0	-	NA	NA	UN	( 6, 28)

B. Other candidate LHON mutations found as single family or singleton cases.

Mutation	NT Δ	AA Δ	AA Cons^a	# Patients	# Controls	Het.^b	Recovery^d	References
m.3472T>C ND1	T-C	F56L	96%	1 case	3	^_	UN	( 22b)
m.4025C>T ND1	C-T	T240M	33%	1 family; 3 cases	0	^_	UN	( 15)
m.4160T>C ND1	T-C	L285P	100%	1 family; 9 cases	1	^_	UN	( 13)
m.4640C>A ND2	C-A	I57M	27%	1 family; 4 cases	0	^_	UN	( 3)
m.5244G>A ND2	G-A	G259S	100%	1 case	0	+	UN	( 1b)
m.9101T>C ATP6	T-C	I192T	13%	1 case	0	^_	UN	( 21)
m.9804G>A CO3	G-A	A200T	93%	Multiple unrelated singleton cases	0	^_	UN	( 14, 17)
m.10237T>C ND3	T-C	I60T	100%	1 family; 2 cases	0	^_	UN	( 9)
m.11253T>C ND4	T-C	I165T	42%	1 case	0	^_	Yes	( 22)
m.11696G>A (ND4) & m.14596A>T (ND6)	G-A A-T	V312I I26M	7% 84%	1 family; 11 cases	0	+	UN	( 5)
m.12811T>C ND5	T-C	Y159H	56%	1 family; 2 cases	0	^_	UN	( 15)
m.12848C>T ND5	C-T	A171V	98%	1 case	0	+	UN	( 23)
m.13637A>G ND5	A-G	Q434R	62%	1 family; 3 cases	0	^_	UN	( 15)
m.13730G>A ND5	G-A	G465E	100%	1 case	0	+	Yes	( 12)
m.14279G>A ND6	G-A	S132L	47%	1 family; 2 cases	0	^_	UN	( 29)
m.14325T>C ND6	T-C	N117D	18%	1 case	0	^_	UN	( 14)
m.14498T>C ND6	T-C	Y59C	98%	1 case	0	+/^_	UN	( 28)
m.14831G>A CytB	G-A	A29T	42%	1 case	0	^_	UN	( 7)

Table Key

a. Conservation calculated using Mitomaster with the species set shown here.

b. Het. = Heteroplasmy; + = detected, - = not detected.

c. NA= not applicable; UN= unknown; penetrance values are rough estimates.

d. Low = anecdotal low degree of vision recovery; Yes = anecdotal moderate to high degree of vision recovery; UN= unknown; NA = not applicable

References

1a. Achilli, A., Iommarini, L., Olivieri, A., Pala, M., Kashani, B. H., et al. (2012). Rare primary mitochondrial DNA mutations and synergistic variants in Leber's Hereditary Optic Neuropathy. PLoS ONE 7(8):e42242.

1b. Brown, M. D., Torroni, A., Reckord, C. L. and Wallace, D. C. (1995). Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Human Mutation 6(4):311-325.

2. Brown, M. D., Voljavec, A. S., Lott, M. T., MacDonald, I. and Wallace, D. C. (1992). Leber's hereditary optic neuropathy: a model for mitochondrial neurodegenerative diseases. FASEB Journal 6(10):2791-2799.

3. Brown, M. D., Zhadanov, S., Allen, J. C., Hosseini, S., Newman, N. J., Atamonov, V. V., Mikhailovskaya, I. E., Sukernik, R. I. and Wallace, D. C. (2001). Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russion LHON families. Human Genetics 109(1):33-39.

4. Chinnery, P. F., Brown, D. T., Andrews, R. M., Singh-Kler, R., Riordan-Eva, P., Lindley, J., Applegarth, D. A., Turnbull, D. M. and Howell, N. (2001). The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy. Brain 124(Pt 1):209-218.

5. De Vries, D. D., Went, L. N., Bruyn, G. W., Scholte, H. R., Hofstra, R. M., Bolhuis, P. A. and van Oost, B. A. (1996). Genetic and biochemical impairment of mitochondrial complex I activity in a family with Leber hereditary optic neuropathy and hereditary spastic dystonia. American Journal of Human Genetics 58(4):703-711.

5b. Dombi, E., Diot, A., Morten, K., Carver, J., Lodge, T., Fratter, C., Ng, Y. S., Liao, C., Muir, R., Blakely, E. L., Hargreaves, I., Al-Dosary, M., Sarkar, G., Hickman, S. J., Downes, S. M., Jayawant, S., Yu-Wai-Man, P., Taylor, R. W. and Poulton, J. (2016). The m.13051G>A mitochondrial DNA mutation results in variable neurology and activated mitophagy. Neurology 86(20):1921-1923.

5c. Emperador, S., Vidal, M., Hernandez-Ainsa, C., Ruiz-Ruiz, C., Woods, D., Morales-Becerra, A., Arruga, J., Artuch, R., Lopez-Gallardo, E., Bayona-Bafaluy, M. P., Montoya, J. and Ruiz-Pesini, E. (2018). The decrease in mitochondrial DNA mutation load parallels visual recovery in a Leber Hereditary Optic Neuropathy patient. Frontiers in Neuroscience 12:61.

6. Fauser, S., Leo-Kottler, B., Besch, D. and Luberichs, J. (2002). Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber's hereditary optic neuropathy. Ophthalmic Genetics 23(3):191-197.

7. Fauser, S., Luberichs, J., Besch, D. and Leo-Kottler, B. (2002). Sequence analysis of the complete mitochondrial genome in patients with Leber's hereditary optic neuropathy lacking the three most common pathogenic DNA mutations. Biochemical and Biophysical Research Communications 295(2):342-347.

8. Gropman, A., Chen, T. J., Perng, C. L., Krasnewich, D., Chernoff, E., Tifft, C. and Wong, L. J. (2004). Variable clinical manifestation of homoplasmic G14459A mitochondrial DNA mutation. American Journal of Medical Genetics 124A(4):377-382.

9. Horvath, J., Horvath, R., Karcagi, V., Komoly, S. and Johns, D. R. (2002). Sequence analysis of Hungarian LHON patients not carrying the common primary mutations. Journal of Inherited Metabolic Disease 25(4):323-324.

10. Howell, N., Bindoff, L. A., McCullough, D. A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L. and Turnbull, D. M. (1991). Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. American Journal of Human Genetics 49(5):939-950.

11. Howell, N., Bogolin, C., Jamieson, R., Marenda, D. R. and Mackey, D. A. (1998). mtDNA mutations that cause optic neuropathy: how do we know? American Journal of Human Genetics 62(1):196-202.

12. Howell, N., Halvorson, S., Burns, J., McCullough, D. A. and Poulton, J. (1993). When does bilateral optic atrophy become Leber hereditary optic atrophy? [letter]. American Journal of Human Genetics 53(4):959-963.

13. Howell, N., Kubacka, I., Xu, M. and McCullough, D. A. (1991). Leber hereditary optic neuropathy: involvement of the mitochondrial ND1 gene and evidence for an intragenic suppressor mutation. American Journal of Human Genetics 48(5):935-942.

14. Howell, N., Oostra, R. J., Bolhuis, P. A., Spruijt, L., Clarke, L. A., Mackey, D. A., Preston, G. and Herrnstadt, C. (2003). Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.9/16 American Journal of Human Genetics 72(6):1460-1469.

15. Huoponen, K., Lamminen, T., Juvonen, V., Aula, P., Nikoskelainen, E. and Savontaus, J. L. (1993). The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy . Human Genetics 92(4):379-384.

16. Huoponen, K., Vilkki, J., Aula, P., Nikoskelainen, E. K. and Savontaus, M. L. (1991). A new mtDNA mutation associated with Leber hereditary optic neuroretinopathy. American Journal of Human Genetics 48(6):1147-1153.

17. Johns, D. R. and Neufeld, M. J. (1993). Cytochrome c oxidase mutations in Leber hereditary optic neuropathy. Biochemical and Biophysical Research Communications 196(2):810-815.

18. Johns, D. R., Neufeld, M. J. and Park, R. D. (1992). An ND-6 mitochondrial DNA mutation associated with Leber hereditary optic neuropathy. Biochemical and Biophysical Research Communications 187(3):1551-1557.

19. Jun, A. S., Brown, M. D. and Wallace, D. C. (1994). A mitochondrial DNA mutation at np 14459 of the ND6 gene associated with maternally inherited Leber's hereditary optic neuropathy and dystonia. Proceedings of the National Academy of Sciences of the United States of America 91(13):6206-6210.

20. Kim, J. Y., Hwang, J. M. and Park, S. S. (2002). Mitochondrial DNA C4171A/ND1 is a novel primary causative mutation of Leber's hereditary optic neuropathy with a good prognosis. Annals of Neurology 51(5):630-634.

21. Lamminen, T., Majander, A., Juvonen, V., Wikstrom, M., Aula, P., Nikoskelainen, E. and Savontous, M. L. (1995). A mitochondrial mutation at nt 9101 in the ATP synthase 6 gene associated with deficient oxidative phosphorylation in a family with Leber hereditary optic neuroretinopathy [letter]. American Journal of Human Genetics 56(5):1238-1240.

22. Leo-Kottler, B., Luberichs, J., Besch, D., Christ-Adler, M. and Fauser, S. (2002). Leber's hereditary optic neuropathy: clinical and molecular genetic results in a patient with a point mutation at np T11253C (isoleucine to threonine) in the ND4 gene and spontaneous recovery. Graefes Archive for Clincial and Experimental Ophthalmology 240(9):758-764.

22b. Martinez-Romero, I., Herrero-Martin, M. D., Llobet, L., Emperador, S., Martin-Navarro, A., Narberhaus, B., Ascaso, F. J., Lopez-Gallardo, E., Montoya, J. and Ruiz-Pesini, E. (2014). New MT-ND1 pathologic mutation for Leber hereditary optic neuropathy. Clinical and Experimental Ophthalmology 42(9):856-864.

23. Mayorov, V., Biousse, V., Newman, N. J. and Brown, M. D. (2005). The role of the ND5 gene in LHON: Characterization of a new, heteroplasmic LHON mutation. Annals of Neurology 58(5):807-811.

23b. Ng, Y. S., Lax, N. Z., Maddison, P., Alston, C. L., Blakely, E. L., et al. (2018). MT-ND5 mutation exhibits highly variable neurological manifestations at low mutant load. EBioMedicine, ePub ahead of print, http://dx.doi.org/10.1016/j.ebiom.2018.02.010

24. Shoffner, J. M., Brown, M. D., Stugard, C., Jun, A. S., Pollok, S., Haas, R. H., Kaufman, A., Koontz, D., Kim, Y., Graham, J., Smith, E., Dixon, J. and Wallace, D. C. (1995). Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation in a complex I subunit. Annals of Neurology 38(2):163-169.

25. Valentino, M. L., Avoni, P., Barboni, P., Pallotti, F., Rengo, C., Torroni, A., Bellan, M., Baruzzi, A. and Carelli, V. (2002). Mitochondrial DNA nucleotide changes C14482G and C14482A in the ND6 gene are pathogenic for Leber's hereditary optic neuropathy. Annals of Neurology 51(6):774-778.

26. Valentino, M. L., Barboni, P., Ghelli, A., Bucchi, L., Rengo, C., Achilli, A., Torroni, A., Lugaresi, A., Lodi, R., Barbiroli, B., Dotti, M., Federico, A., Baruzzi, A. and Carelli, V. (2004). The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. Annals of Neurology 56(5):631-641.

27. Wallace, D. C., Singh, G., Lott, M. T., Hodge, J. A., Schurr, T. G., Lezza, A. M., Elsas, L. J. and Nikoskelainen, E. K. (1988). Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242(4884):1427-1430.

28. Wissinger, B., Besch, D., Baumann, B., Fauser, S., Christ-Adler, M., Jurklies, B., Zrenner, E. and Leo-Kottler, B. (1997). Mutation analysis of the ND6 gene in patients with Lebers hereditary optic neuropathy. Biochemical & Biophysical Research Communications 234(2):511-515.

29. Zhadanov, S. I., Atamanov, V. V., Zhadanov, N. I., Oleinikov, O. V., Osipova, L. P. and Schurr, T. G. (2005). A novel mtDNA ND6 gene mutation associated with LHON in a Caucasian family. Biochemical and Biophysical Research Communications 332(4):1115-1121.

30. Zhang, S., Wang, L., Hao, Y., Wang, P., Hao, P., Yin, K., Wang, Q. K. and Liu, M. (2008). "T14484C and T14502C in the mitochondrial ND6 gene are associated with Leber's hereditary optic neuropathy in a Chinese family". Mitochondrion 8(3):205-210.

31. Zhao, F., Guan, M., Zhou, X., Yuan, M., Liang, M., Liu, Q., Liu, Y., Zhang, Y., Yang, L., Tong, Y., Wei, Q. P., Sun, Y. H., Qu, J. and Guan, M. X. (2009). "Leber's hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation". Biochemical and Biophysical Research Communications 389(3):466-472.

32. Spruijt, L., Smeets, H. J., Hendrickx, A., Bettink-Remeijer, M. W., Maat-Kievit, A., Schoonderwoerd, K. C., Sluiter, W., de Coo, I. F. and Hintzen, R. Q. (2007). "A MELAS-associated ND1 mutation causing leber hereditary optic neuropathy and spastic dystonia." Archives of Neurology 64(6):890-893.

33. Blakely, E. L., de Silva, R., King, A., Schwarzer, V., Harrower, T., Dawidek, G., Turnbull, D. M. and Taylor, R. W. (2005). "LHON/MELAS overlap syndrome associated with a mitochondrial MTND1 gene mutation." European Journal of Human Genetics 13(5):623-627.

34. Yu-Wai-Man, P., Griffiths, P. G., Hudson, G. and Chinnery, P. F. (2009). "Inherited mitochondrial optic neuropathies [Review]." Journal of Medical Genetics 46(3):145-158.

35. Patsi, J., Maliniemi, P., Pakanen, S., Hinttala, R., Uusimaa, J., Majamaa, K., Nystrom, T., Kervinen, M. and Hassinen, I. E. (2012). "LHON/MELAS overlap mutation in ND1 subunit of mitochondrial complex I affects ubiquinone binding as revealed by modeling in Escherichia coli NDH-1." Biochimica et Biophysica Acta 1817(2):312-318.

36. Wang, K., Takahashi, Y., Gao, Z. L., Wang, G. X., Chen, X. W., Goto, J., Lou, J. N. and Tsuji, S. (2009). "Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia." Neurogenetics 10(4):337-345.

Topic revision: r6 - 19 Mar 2018, MarieLott

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