Leber's Hereditary Optic Neuropathy (LHON) Disease Mutations

A. "Top 14" 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 ∆

AA ∆

AA
Consa

% Patients

% Controls

Het.b

Penetrancec
% Relatives

Penetrancec
%

Males

% Recoveryd

References

MTND4*LHON11778A

G-A

R340H

H

69

0

+/-

33-60

82

4

(27)

MTND1*LHON3460A

G-A

A52T

M

13

0

+/-

14-75

40-80

22

(10, 16)

MTND6*LHON14484C

T-C

M64V

L

14

0

+/-

27-80

68

37-65

(2, 13, 18)

MTND1*LHON3635A

G-A

S110N

H

Rare

0

+/-

29
(range 11-64)

54
(range 25-100)

Low

(3)

MTND1*LHON3700A

G-A

A112T

H

Rare

0

-

NA

NA

UN

(1a,7)

MTND1*LHON3733A

G-A

E143K

H

Rare

0

+/-

24-30

36-44

Yes

(1a, 26)

MTND1*LHON4171A

C-A

L289M

H

Rare

0

+/-

46

47

Yes

(20)

MTND4L*LHON10663C

T-C

V65A

L

Rare

0

-

56

60

UN

(1a,1b)

MTND6*LDYT14459A

G-A

A72V

M

Rare

0

+

NA

NA

Low

(8, 19, 24)

MTND6*LHON14482A

C-A

M64I

L

Rare

0

+/-

NA

89

Yes

(1a,25)

MTND6*LHON14482G

C-G

M64I

L

Rare

0

-

NA

NA

UN

(11)

MTND6*LHON14495G

A-G

L60S

H

Rare

0

+

NA

NA

Low

(4)

MTND6*LHON14502C

T-C

I58V

H

Rare

0

-

14502:10%
14502+11778:37%

14502:11%
14502+11778:47%

UN

(1a, 30, 31)

MTND6*LHON14568T

C-T

G36S

M

Rare

0

-

NA

NA

UN

(6, 28)

 

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

Mutation

Nt

AA ∆

AA
Consa

#
Patients

# Controls

Het.b

Recoveryd

References

MTND1*LHON4025T

C-T

T240M

M

1 family; 3 cases

0

_

UN

(15)

MTND2*LHON5244A

G-A

G259S

H

1 case

0

+

UN

(1b)

MTND2*LHON4640A

C-A

I57M

L

1 family; 4 cases

0

_

UN

(3)

MTND3*LHON10237C

T-C

I60T

H

1 family; 2 cases

0

_

UN

(9)

MTND4*LHON11253C

T-C

I165T

H

1 case

0

_

Yes

(22)

MTND4*LDYT11696G/
MTND6*LDYT14596A

A-G
G-A

V312I
I26M

L
M

1 family; 11 cases

0

+
_

UN

(5)

MTND5*LHON12811C

T-C

Y159H

M

1 family; 2 cases

0

_

UN

(15)

MTND5*LHON12848T

C-T

A171V

H

1 case

0

+

UN

(23)

MTND5*LHON13051A

G-A

G239S

H

1 family; 3 cases

0

_

UN

(14)

MTND5*LHON13637G

A-G

Q434R

L

1 family; 3 cases

0

_

UN

(15)

MTND5*LHON13730A

G-A

G465E

M

1 case

0

+

Yes

(12)

MTND6*LHON14279A

G-A

S132L

M

1 family; 2 cases

0

_

UN

(29)

MTND6*LHON14325C

T-C

N117D

L

1 case

0

_

UN

(14)

MTND6*LHON14498T

C-T

Y59C

M

1 case

0

+/_

UN

(28)

MTATP6*LHON9101C

T-C

I192T

L

1 case

0

_

UN

(21)

MTCO3*LHON9804A

G-A

A200T

H

Multiple unrelated
singleton cases

0

_

UN

(14, 17)

MTCYB*LHON14831A

G-A

A29T

M

1 case

0

_

UN

(7)

Table Key

  • a. H= high amino acid conservation, M= moderate; L= low; NA= not applicable; Ter= termination codon.
  • 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.

    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. 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.

    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.

    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.


    This table is an updated version of the one originally found in and used with permission from PRINCIPLES AND PRACTICE OF MEDICAL GENETICS, 5/e. © 2006 Elsevier Ltd.

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