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Previously unclassified mutation of mtDNA m.3472T>C: Evidence of pathogenicity in Leber’s hereditary optic neuropathy

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Abstract

Leber’s hereditary optic neuropathy (LHON) refers to a group of mitochondrial diseases and is characterized by defects of the mitochondrial electron transport chain and decreased level of oxidative phosphorylation. The list of LHON primary mtDNA mutations is regularly updated. In this study, we describe the homoplasmic nucleotide substitution m.3472T>C in the MT-ND1 (NADH-ubiquinone oxidoreductase chain 1) gene and specific changes in cell metabolism in a patient with LHON and his asymptomatic sister. To confirm the presence of mutation-related mitochondrial dysfunction, respiration of skin fibroblasts and platelets from the patient and his sister was studied, as well as the mitochondrial potential and production of reactive oxygen species in the skin fibroblasts. In addition, based on characteristics of the toxic effect of paraquat, a new approach was developed for detecting the functional activity of complex I of the mitochondrial respiratory chain.

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Abbreviations

LHON:

Leber’s hereditary optic neuropathy

MLPA method:

Multiplex Ligase-dependent Probe Amplification respirometry

mtDNA:

mitochondrial DNA

NGS:

Next-Generation Sequencing

ROS:

reactive oxygen species

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Authors and Affiliations

  1. Research Institute of Eye Diseases, 119021, Moscow, Russia

    N. L. Sheremet, T. A. Nevinitsyna, N. V. Zhorzholadze, I. A. Ronzina & S. E. Avetisov

  2. Research Center for Medical Genetics, 115478, Moscow, Russia

    Y. S. Itkis, T. D. Krylova, P. G. Tsygankova, V. A. Malakhova & E. Y. Zakharova

  3. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. V. Tokarchuk, A. A. Panteleeva, E. M. Karger & K. G. Lyamzaev

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  1. N. L. Sheremet
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  2. T. A. Nevinitsyna
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  14. S. E. Avetisov
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Correspondence to N. L. Sheremet.

Additional information

Original Russian Text © N. L. Sheremet, T. A. Nevinitsyna, N. V. Zhorzholadze, I. A. Ronzina, Y. S. Itkis, T. D. Krylova, P. G. Tsygankova, V. A. Malakhova, E. Y. Zakharova, A. V. Tokarchuk, A. A. Panteleeva, E. M. Karger, K. G. Lyamzaev, S. E. Avetisov, 2016, published in Biokhimiya, 2016, Vol. 81, No. 7, pp. 982-990.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM16-078, May 16, 2016.

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Sheremet, N.L., Nevinitsyna, T.A., Zhorzholadze, N.V. et al. Previously unclassified mutation of mtDNA m.3472T>C: Evidence of pathogenicity in Leber’s hereditary optic neuropathy. Biochemistry Moscow 81, 748–754 (2016). https://doi.org/10.1134/S0006297916070117

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  • DOI: https://doi.org/10.1134/S0006297916070117

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