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Gene Review

LHON  -  Leber optic neuropathy

Homo sapiens

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Disease relevance of LHON

  • The Tas2 and Vic2 Australian families are affected with a variant of Leber hereditary optic neuropathy (LHON) [1].
  • The risk of developing the optic neuropathy shows strict maternal inheritance, and the ophthalmological changes in affected family members are characteristic of LHON [1].
  • Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, MELAS and LHON collectively) patients and in LHON patients differed significantly from controls (P < or = 0.05, t) [2].
  • These results imply that biochemical studies on mitochondrial diseases should always be integrated with mtDNA analysis of the same tissue investigated and also suggest that the mtDNA analysis on the leukocyte fraction, as usually performed in LHON, does not necessarily reflect the mutant genotype level of other tissues [3].
  • Taken together with the sex bias in symptom manifestation, the results indirectly suggest that an extramitochondrial factor, such as an X-chromosome-linked gene, possibly contributes to the development of optic atrophy in the Japanese LHON pedigrees tested [4].

Psychiatry related information on LHON

  • However, six of the LHON patients had frequent alcohol consumption, while none of the asymptomatic carriers claimed frequent drinking habit [5].

High impact information on LHON


Chemical compound and disease context of LHON


Biological context of LHON

  • One possibility is that there is a primary LHON mutation within the mitochondrial genome but that it is at a site that was not included in the sequencing analyses [1].
  • Biochemical and molecular genetic evidence is presented that in six independent pedigrees the development of Leber hereditary optic neuropathy (LHON) is due to the same primary mutation in the mitochondrial ND1 gene [14].
  • Four different but related mitochondrial genotypes were identified in seven of the Dutch pedigrees with LHON, including six of those described by van Senus [15].
  • These studies provide the first direct evidence that not all LHON lineages--even those associated with a biochemical defect in mitochondrial respiratory chain Complex I--carry a mutation in the ND4 gene [16].
  • This is only the second instance in which both a biochemical abnormality and a mitochondrial gene mutation have been identified in an LHON pedigree [14].

Anatomical context of LHON

  • Leber's hereditary optic neuropathy (LHON) is a common cause of bilateral optic nerve disease [17].
  • In conclusion, LHON cybrid cells forced by the reduced rate of glycolytic flux to utilize oxidative metabolism are sensitized to an apoptotic death through a mechanism involving mitochondria [9].
  • Moreover, we also document the mitochondrial involvement in the activation of the apoptotic cascade, as shown by the increased release of cytochrome c into the cytosol in LHON cybrid cells as compared with controls [9].
  • No previous study has investigated the effects of LHON primary or primary plus secondary mutations on the respiratory competence of cell lines [18].
  • Total lymphocyte DNA was analyzed for all common LHON mutations [19].

Associations of LHON with chemical compounds

  • Similarly, the rate of muscle phosphocreatine resynthesis after exercise, a sensitive index of the rate of mitochondrial ATP production, was reduced by the same extent in both groups of LHON subjects [20].
  • In conclusion, the caspase-independent death of LHON cybrids incubated in galactose medium is triggered by rapid ATP depletion and mediated by AIF and EndoG [21].
  • The glutamate uptake maximal velocity was significantly reduced in all LHON cybrids compared with control cybrids [22].
  • The new sequence variant of A9016G in the ATPase 6 gene changed highly conserved amino acid of isoleucine to valine, has not been found in the rest of 13 LHON patients and controls [23].
  • We report that this amino acid substitution alters the affinity of complex I for the ubiquinone substrate and induces resistance towards its potent inhibitor rotenone in mitochondria of LHON patients [24].

Physical interactions of LHON

  • The same gene was also reported to carry another mutation, at position 14459, associated with the LHON/dystonia phenotype that induces a reduction of complex I-specific activity and increases the sensitivity to the product decylubiquinol [25].
  • METHODS: Assays for the activities of NADH-cytochrome c reductase (complex I+complex III), succinate-cytochrome c reductase (complex II+complex III), and cytochrome c oxidase (complex IV) on blood cell mitochondria of seven LHON patients and 15 normal controls [26].

Regulatory relationships of LHON

  • However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON [27].
  • Secondary LHON mutations were identified more frequently in control subjects than in the children with MS [28].

Other interactions of LHON

  • We conclude that the 3733G-->A transition is a novel cause of LHON and, after those at positions 3460 and 4171, is the third ND1 mutation to be identified in multiple unrelated families [29].
  • In contrast, in galactose, GSSG concentrations increased significantly in all cells, indicating severe oxidative stress, whereas GR and MnSOD activities further decreased in all LHON cybrids [30].
  • The sequence analysis of the ND81 gene was extended to a further 11, unrelated LHON pedigrees that had been screened previously and found not to carry the mitochondrial ND4/R340H mutation [14].
  • We report the effect on complex I function of the 14484 Leber's hereditary optic neuropathy (LHON) mutation affecting the ND6 subunit gene [25].
  • Similarly, complex IV mutation COI/7444 was screened in Finnish LHON families, and it was found in one family carrying the ND1/3460 mutation [31].

Analytical, diagnostic and therapeutic context of LHON


  1. A variant of Leber hereditary optic neuropathy characterized by recovery of vision and by an unusual mitochondrial genetic etiology. Mackey, D., Howell, N. Am. J. Hum. Genet. (1992) [Pubmed]
  2. Mitochondrial DNA polymorphism in disease: a possible contributor to respiratory dysfunction. Lertrit, P., Kapsa, R.M., Jean-Francois, M.J., Thyagarajan, D., Noer, A.S., Marzuki, S., Byrne, E. Hum. Mol. Genet. (1994) [Pubmed]
  3. Leber's hereditary optic neuropathy: biochemical effect of 11778/ND4 and 3460/ND1 mutations and correlation with the mitochondrial genotype. Carelli, V., Ghelli, A., Ratta, M., Bacchilega, E., Sangiorgi, S., Mancini, R., Leuzzi, V., Cortelli, P., Montagna, P., Lugaresi, E., Degli Esposti, M. Neurology (1997) [Pubmed]
  4. Homoplasmic and exclusive ND4 gene mutation in Japanese pedigrees with Leber's disease. Nakamura, M., Fujiwara, Y., Yamamoto, M. Invest. Ophthalmol. Vis. Sci. (1993) [Pubmed]
  5. Genotypes of aldehyde dehydrogenase and alcohol dehydrogenase polymorphisms in patients with Leber's hereditary optic neuropathy. Isashiki, Y., Tabata, Y., Kamimura, K., Ohba, N. Jpn. J. Hum. Genet. (1997) [Pubmed]
  6. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Delettre, C., Lenaers, G., Griffoin, J.M., Gigarel, N., Lorenzo, C., Belenguer, P., Pelloquin, L., Grosgeorge, J., Turc-Carel, C., Perret, E., Astarie-Dequeker, C., Lasquellec, L., Arnaud, B., Ducommun, B., Kaplan, J., Hamel, C.P. Nat. Genet. (2000) [Pubmed]
  7. Pre-excitation syndrome in Leber's hereditary optic neuropathy. Nikoskelainen, E.K., Savontaus, M.L., Huoponen, K., Antila, K., Hartiala, J. Lancet (1994) [Pubmed]
  8. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Carelli, V., Achilli, A., Valentino, M.L., Rengo, C., Semino, O., Pala, M., Olivieri, A., Mattiazzi, M., Pallotti, F., Carrara, F., Zeviani, M., Leuzzi, V., Carducci, C., Valle, G., Simionati, B., Mendieta, L., Salomao, S., Belfort, R., Sadun, A.A., Torroni, A. Am. J. Hum. Genet. (2006) [Pubmed]
  9. Leber's hereditary optic neuropathy (LHON) pathogenic mutations induce mitochondrial-dependent apoptotic death in transmitochondrial cells incubated with galactose medium. Ghelli, A., Zanna, C., Porcelli, A.M., Schapira, A.H., Martinuzzi, A., Carelli, V., Rugolo, M. J. Biol. Chem. (2003) [Pubmed]
  10. Changes in mitochondrial complex I activity and coenzyme Q binding site in Leber's hereditary optic neuropathy (LHON). Ghelli, A., Degli Esposti, M., Carelli, V., Lenaz, G. Mol. Aspects Med. (1997) [Pubmed]
  11. Wolfram (DIDMOAD) syndrome and Leber hereditary optic neuropathy (LHON) are associated with distinct mitochondrial DNA haplotypes. Hofmann, S., Bezold, R., Jaksch, M., Obermaier-Kusser, B., Mertens, S., Kaufhold, P., Rabl, W., Hecker, W., Gerbitz, K.D. Genomics (1997) [Pubmed]
  12. Adenosine triphosphate deficiency: a genre of optic neuropathy. Rizzo, J.F. Neurology (1995) [Pubmed]
  13. Partial mitochondrial complex I inhibition induces oxidative damage and perturbs glutamate transport in primary retinal cultures. Relevance to Leber Hereditary Optic Neuropathy (LHON). Beretta, S., Wood, J.P., Derham, B., Sala, G., Tremolizzo, L., Ferrarese, C., Osborne, N.N. Neurobiol. Dis. (2006) [Pubmed]
  14. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Howell, N., Bindoff, L.A., McCullough, D.A., Kubacka, I., Poulton, J., Mackey, D., Taylor, L., Turnbull, D.M. Am. J. Hum. Genet. (1991) [Pubmed]
  15. Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy. Howell, N., Oostra, R.J., Bolhuis, P.A., Spruijt, L., Clarke, L.A., Mackey, D.A., Preston, G., Herrnstadt, C. Am. J. Hum. Genet. (2003) [Pubmed]
  16. An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene. Howell, N., McCullough, D. Am. J. Hum. Genet. (1990) [Pubmed]
  17. The mitochondrial ND6 gene is a hot spot for mutations that cause Leber's hereditary optic neuropathy. Chinnery, P.F., Brown, D.T., Andrews, R.M., Singh-Kler, R., Riordan-Eva, P., Lindley, J., Applegarth, D.A., Turnbull, D.M., Howell, N. Brain (2001) [Pubmed]
  18. MtDNA mutations associated with Leber's hereditary optic neuropathy: studies on cytoplasmic hybrid (cybrid) cells. Vergani, L., Martinuzzi, A., Carelli, V., Cortelli, P., Montagna, P., Schievano, G., Carrozzo, R., Angelini, C., Lugaresi, E. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  19. 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. Leo-Kottler, B., Luberichs, J., Besch, D., Christ-Adler, M., Fauser, S. Graefes Arch. Clin. Exp. Ophthalmol. (2002) [Pubmed]
  20. 'Secondary' 4216/ND1 and 13708/ND5 Leber's hereditary optic neuropathy mitochondrial DNA mutations do not further impair in vivo mitochondrial oxidative metabolism when associated with the 11778/ND4 mitochondrial DNA mutation. Lodi, R., Montagna, P., Cortelli, P., Iotti, S., Cevoli, S., Carelli, V., Barbiroli, B. Brain (2000) [Pubmed]
  21. Caspase-independent death of Leber's hereditary optic neuropathy cybrids is driven by energetic failure and mediated by AIF and Endonuclease G. Zanna, C., Ghelli, A., Porcelli, A.M., Martinuzzi, A., Carelli, V., Rugolo, M. Apoptosis (2005) [Pubmed]
  22. Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines. Beretta, S., Mattavelli, L., Sala, G., Tremolizzo, L., Schapira, A.H., Martinuzzi, A., Carelli, V., Ferrarese, C. Brain (2004) [Pubmed]
  23. A new sequence variant in mitochondrial DNA associated with high penetrance of Russian Leber hereditary optic neuropathy. Povalko, N., Zakharova, E., Rudenskaia, G., Akita, Y., Hirata, K., Toyojiro, M., Koga, Y. Mitochondrion (2005) [Pubmed]
  24. Functional alterations of the mitochondrially encoded ND4 subunit associated with Leber's hereditary optic neuropathy. Degli Esposti, M., Carelli, V., Ghelli, A., Ratta, M., Crimi, M., Sangiorgi, S., Montagna, P., Lenaz, G., Lugaresi, E., Cortelli, P. FEBS Lett. (1994) [Pubmed]
  25. Biochemical features of mtDNA 14484 (ND6/M64V) point mutation associated with Leber's hereditary optic neuropathy. Carelli, V., Ghelli, A., Bucchi, L., Montagna, P., De Negri, A., Leuzzi, V., Carducci, C., Lenaz, G., Lugaresi, E., Degli Esposti, M. Ann. Neurol. (1999) [Pubmed]
  26. Compensatory elevation of complex II activity in Leber's hereditary optic neuropathy. Yen, M.Y., Lee, H.C., Liu, J.H., Wei, Y.H. The British journal of ophthalmology. (1996) [Pubmed]
  27. mtDNA haplotype analysis in Finnish families with leber hereditary optic neuroretinopathy. Lamminen, T., Huoponen, K., Sistonen, P., Juvonen, V., Lahermo, P., Aula, P., Nikoskelainen, E., Savontaus, M.L. Eur. J. Hum. Genet. (1997) [Pubmed]
  28. Characterization of the mitochondrial genome in childhood multiple sclerosis. II. Multiple sclerosis without optic neuritis and LHON-associated genes. Wilichowski, E., Ohlenbusch, A., Hanefeld, F. Neuropediatrics. (1998) [Pubmed]
  29. The ND1 gene of complex I is a mutational hot spot for Leber's hereditary optic neuropathy. 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., Carelli, V. Ann. Neurol. (2004) [Pubmed]
  30. Antioxidant defences in cybrids harboring mtDNA mutations associated with Leber's hereditary optic neuropathy. Floreani, M., Napoli, E., Martinuzzi, A., Pantano, G., De Riva, V., Trevisan, R., Bisetto, E., Valente, L., Carelli, V., Dabbeni-Sala, F. FEBS J. (2005) [Pubmed]
  31. The spectrum of mitochondrial DNA mutations in families with Leber hereditary optic neuroretinopathy. Huoponen, K., Lamminen, T., Juvonen, V., Aula, P., Nikoskelainen, E., Savontaus, M.L. Hum. Genet. (1993) [Pubmed]
  32. Molecular diagnosis of Leber's hereditary optic neuropathy. Yen, M.Y., Liu, J.H., Pang, C.Y., Wei, Y.H. J. Formos. Med. Assoc. (1993) [Pubmed]
  33. Time-resolved fluorometry in the diagnosis of Leber hereditary optic neuroretinopathy. Huoponen, K., Juvonen, V., Iitiä, A., Dahlen, P., Siitari, H., Aula, P., Nikoskelainen, E., Savontaus, M.L. Hum. Mutat. (1994) [Pubmed]
  34. A case-control study of Leber's hereditary optic neuropathy. Charlmers, R.M., Harding, A.E. Brain (1996) [Pubmed]
  35. Analysis of mitochondrial DNA in Leber's hereditary optic neuropathy. Poulton, J., Deadman, M.E., Bronte-Stewart, J., Foulds, W.S., Gardiner, R.M. J. Med. Genet. (1991) [Pubmed]
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