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Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia

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Abstract

Leber hereditary optic neuropathy and dystonia (LDYT) is a mitochondrial disorder associated with variable combinations of vision loss and progressive generalized dystonia. LDYT is a unique oxidative phosphorylation disorder caused by mutations in mitochondrial ND6 or ND4 gene. In this paper, we describe a Chinese family with 18 LDYT patients. The comprehensive nucleotide sequence analysis of the entire mitochondrial genome using resequencing microarray revealed a mutation (mtND3*10197A (m.10197G>A)) substituting a threonine for a highly conserved alanine at codon 47 of MTND3 on the background of haplogroup D4b. Quantitative analysis of the heteroplasmy of the mutation revealed a homoplasmy in the leukocytes of all the affected individuals on the maternal side. This is the first description of the ND3 mutation causing LDYT. The mtND3*10197A (m.10197G>A) mutation has recently been described in French and Korean patients with Leigh syndrome. These findings suggest that the clinical presentations associated with the mtND3*10197A (m.10197G>A) mutation (ND3) are much wider, encompassing those of LDYT and Leigh syndrome.

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Acknowledgment

This work was supported by the National Natural Science Foundation of China (grant no. 30270478) and a grant from the Ministry of Health of China. This work was supported in part by KAKENHI (Grant-in-Aid for Scientific Research) on Priority Areas, Applied Genomics, the 21st Century COE Program, Center for Integrated Brain Medical Science, and Scientific Research (A) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for “the Research Committee for Ataxic Diseases” of the Research on Measures for Intractable Diseases from the Ministry of Health, Labour and Welfare, Japan, and a grant from the Takeda Science Foundation. We also thank the family members for their cooperation, Deoka Ken for his assistances in molecular biological techniques, and Prof. Cheng Zhang for his research advice.

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Authors and Affiliations

  1. Department of Pathology and Pathophysiology, Graduate School, Peking Union Medical College, Beijing, China

    Kang Wang, Guo-Xiang Wang & Jin-Ning Lou

  2. Department of Neurology, China–Japan Friendship Hospital, Beijing, China

    Kang Wang

  3. Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Kang Wang, Yuji Takahashi, Jun Goto & Shoji Tsuji

  4. Department of Neurology, First Affiliated Hospital, Anhui Medical University, Hefei, China

    Zong-Liang Gao & Xian-Wen Chen

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  1. Kang Wang
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Correspondence to Shoji Tsuji.

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Supplementary Table 1

PCR and primer pairs (PPT 75 kb)

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Wang, K., Takahashi, Y., Gao, ZL. et al. Mitochondrial ND3 as the novel causative gene for Leber hereditary optic neuropathy and dystonia. Neurogenetics 10, 337–345 (2009). https://doi.org/10.1007/s10048-009-0194-0

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