Human Genetics

, Volume 109, Issue 1, pp 33–39 | Cite as

Novel mtDNA mutations and oxidative phosphorylation dysfunction in Russian LHON families

  • Michael D. Brown
  • Sergei Zhadanov
  • Jon C. Allen
  • Seyed Hosseini
  • Nancy J. Newman
  • Vasily V. Atamonov
  • Irina E. Mikhailovskaya
  • Rem I. Sukernik
  • Douglas C. Wallace
Original Investigation

Abstract.

Leber's hereditary optic neuropathy (LHON) is characterized by maternally transmitted, bilateral, central vision loss in young adults. It is caused by mutations in the mitochondrial DNA (mtDNA) encoded genes that contribute polypeptides to NADH dehydrogenase or complex I. Four mtDNA variants, the nucleotide pair (np) 3460A, 11778A, 14484C, and 14459A mutations, are known as "primary" LHON mutations and are found in most, but not all, of the LHON families reported to date. Here, we report the extensive genetic and biochemical analysis of five Russian families from the Novosibirsk region of Siberia manifesting maternally transmitted optic atrophy consistent with LHON. Three of the five families harbor known LHON primary mutations. Complete sequence analysis of proband mtDNA in the other two families has revealed novel complex I mutations at nps 3635A and 4640C, respectively. These mutations are homoplasmic and have not been reported in the literature. Biochemical analysis of complex I in patient lymphoblasts and transmitochondrial cybrids demonstrated a respiration defect with complex-I-linked substrates, although the specific activity of complex I was not reduced. Overall, our data suggests that the spectrum of mtDNA mutations associated with LHON in Russia is similar to that in Europe and North America and that the np 3635A and 4640C mutations may be additional mtDNA complex I mutations contributing to LHON expression.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Copyright information

© Springer-Verlag 2001

Authors and Affiliations

  • Michael D. Brown
    • 1
  • Sergei Zhadanov
    • 3
  • Jon C. Allen
    • 1
  • Seyed Hosseini
    • 1
  • Nancy J. Newman
    • 2
  • Vasily V. Atamonov
    • 4
  • Irina E. Mikhailovskaya
    • 4
  • Rem I. Sukernik
    • 3
  • Douglas C. Wallace
    • 1
  1. 1.Center for Molecular Medicine, Emory University School of Medicine, 420 B Dental Building, 1462 Clifton Road, N.E. Atlanta, GA 30322, USAUSA
  2. 2.Department of Ophthalmology, Emory University School of Medicine, Atlanta, Ga., USAUSA
  3. 3.Laboratory of Human Molecular Genetics, Institute of Cytology and Genetics, Siberian Division, Russian Academy of Sciences, Novosibirsk, Siberia, RussiaRussia
  4. 4.Regional Center of Eye Microsurgery, Novosibirsk, Siberia, RussiaRussia

Personalised recommendations