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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1990 Oct;47(4):629–634.

An example of Leber hereditary optic neuropathy not involving a mutation in the mitochondrial ND4 gene.

N Howell 1, D McCullough 1
PMCID: PMC1683808  PMID: 2121024

Abstract

A large Australian family afflicted with Leber's Hereditary Optic Neuropathy (LHON) is analyzed at the nucleotide sequence level in this report. Biochemical assays of platelet mitochondria isolated from members of this family have demonstrated a significant decrease in the specific activity of Complex I (NADH-ubiquinol oxidoreductase) of the electron transport chain. It is shown here, however, that neither this biochemical lesion nor the optic neuropathy are due to the mutation at nucleotide position 11,778 of the mitochondrial ND4 gene first identified by Wallace et al. in several LHON pedigrees. Furthermore, extensive DNA sequencing studies reveal no candidate mutations within the mitochondrial ND3 gene, the ND4L/ND4 genes, or the contiguous tRNA genes. 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. Members of the Australian LHON family exhibit neurological abnormalities in addition to the well-characterized ophthalmological changes. It is hypothesized that LHON may be a syndrome or set of related diseases in which the clinical abnormalities are a function, at least in part, of the mitochondrial Complex I gene in which the proximate mutation occurs.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams J. H., Blackwood W., Wilson J. Further clinical and pathological observations on Leber's optic atrophy. Brain. 1966 Mar;89(1):15–26. doi: 10.1093/brain/89.1.15. [DOI] [PubMed] [Google Scholar]
  2. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  3. BRUYN G. W., WENT L. N. A SEX-LINKED HEREDO-DEGENERATIVE NEUROLOGICAL DISORDER, ASSOCIATED WITH LEBER'S OPTIC ATROPHY. I. CLINICAL STUDIES. J Neurol Sci. 1964 Jan-Feb;1(1):59–80. doi: 10.1016/0022-510x(64)90054-1. [DOI] [PubMed] [Google Scholar]
  4. Biggin M. D., Gibson T. J., Hong G. F. Buffer gradient gels and 35S label as an aid to rapid DNA sequence determination. Proc Natl Acad Sci U S A. 1983 Jul;80(13):3963–3965. doi: 10.1073/pnas.80.13.3963. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crouse G. F., Frischauf A., Lehrach H. An integrated and simplified approach to cloning into plasmids and single-stranded phages. Methods Enzymol. 1983;101:78–89. doi: 10.1016/0076-6879(83)01006-x. [DOI] [PubMed] [Google Scholar]
  6. Giles R. E., Blanc H., Cann H. M., Wallace D. C. Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6715–6719. doi: 10.1073/pnas.77.11.6715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Holt I. J., Miller D. H., Harding A. E. Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy. J Med Genet. 1989 Dec;26(12):739–743. doi: 10.1136/jmg.26.12.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Howell N., Gilbert K. Mutational analysis of the mouse mitochondrial cytochrome b gene. J Mol Biol. 1988 Oct 5;203(3):607–618. doi: 10.1016/0022-2836(88)90195-7. [DOI] [PubMed] [Google Scholar]
  9. Nikoskelainen E. K., Savontaus M. L., Wanne O. P., Katila M. J., Nummelin K. U. Leber's hereditary optic neuroretinopathy, a maternally inherited disease. A genealogic study in four pedigrees. Arch Ophthalmol. 1987 May;105(5):665–671. doi: 10.1001/archopht.1987.01060050083043. [DOI] [PubMed] [Google Scholar]
  10. Nikoskelainen E. New aspects of the genetic, etiologic, and clinical puzzle of Leber's disease. Neurology. 1984 Nov;34(11):1482–1484. doi: 10.1212/wnl.34.11.1482. [DOI] [PubMed] [Google Scholar]
  11. Parker W. D., Jr, Oley C. A., Parks J. K. A defect in mitochondrial electron-transport activity (NADH-coenzyme Q oxidoreductase) in Leber's hereditary optic neuropathy. N Engl J Med. 1989 May 18;320(20):1331–1333. doi: 10.1056/NEJM198905183202007. [DOI] [PubMed] [Google Scholar]
  12. Rose F. C., Bowden A. N., Bowden P. M. The heart in Leber's optic atrophy. Br J Ophthalmol. 1970 Jun;54(6):388–393. doi: 10.1136/bjo.54.6.388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  14. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Singh G., Lott M. T., Wallace D. C. A mitochondrial DNA mutation as a cause of Leber's hereditary optic neuropathy. N Engl J Med. 1989 May 18;320(20):1300–1305. doi: 10.1056/NEJM198905183202002. [DOI] [PubMed] [Google Scholar]
  16. VANSENUS A. H. LEBER'S DISEASE IN THE NETHERLANDS. Doc Ophthalmol. 1963;17:1–162. doi: 10.1007/BF00573524. [DOI] [PubMed] [Google Scholar]
  17. Vilkki J., Savontaus M. L., Nikoskelainen E. K. Genetic heterogeneity in Leber hereditary optic neuroretinopathy revealed by mitochondrial DNA polymorphism. Am J Hum Genet. 1989 Aug;45(2):206–211. [PMC free article] [PubMed] [Google Scholar]
  18. WENT L. N. A SEX-LINKED HEREDO-DEGENERATIVE NEUROLOGICAL DISORDER ASSOCIATED WITH LEBER'S OPTIC ATROPHY. GENETICAL ASPECTS. Acta Genet Stat Med. 1964;14:220–239. doi: 10.1159/000151849. [DOI] [PubMed] [Google Scholar]
  19. Wallace D. C. A new manifestation of Leber's disease and a new explanation for the agency responsible for its unusual pattern of inheritance. Brain. 1970;93(1):121–132. doi: 10.1093/brain/93.1.121. [DOI] [PubMed] [Google Scholar]
  20. Wallace D. C., Singh G., Lott M. T., Hodge J. A., Schurr T. G., Lezza A. M., Elsas L. J., 2nd, Nikoskelainen E. K. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427–1430. doi: 10.1126/science.3201231. [DOI] [PubMed] [Google Scholar]
  21. Yoneda M., Tsuji S., Yamauchi T., Inuzuka T., Miyatake T., Horai S., Ozawa T. Mitochondrial DNA mutation in family with Leber's hereditary optic neuropathy. Lancet. 1989 May 13;1(8646):1076–1077. doi: 10.1016/s0140-6736(89)92470-7. [DOI] [PubMed] [Google Scholar]

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