Leber’s hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation

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Abstract

We report here the clinical, genetic, and molecular characterization of three Chinese families with Leber’s hereditary optic neuropathy (LHON). There were variable severity and age of onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T14502C (I58V) mutation, which localized at a highly conserved isoleucine at position 58 of ND6, and distinct sets of mtDNA polymorphisms belonging to haplogroups M10a, F1a1, and H2. The occurrence of T14502C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicates that this mutation is involved in the pathogenesis of visual impairment. Here, mtDNA variants I187T in the ND1, A122V in CO1, S99A in the A6, and V254I in CO3 exhibited an evolutionary conservation, indicating a potential modifying role in the development of visual impairment associated with T14502C mutation in those families. Furthermore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic manifestation of the LHON-associated T14502C mutation in these Chinese families.

Introduction

Leber’s hereditary optic neuropathy (LHON) is a maternally inherited eye disease that generally affects young adults with the rapid, painless, bilateral loss of central vision [1], [2], [3]. Mutations in mitochondrial DNA (mtDNA) are the molecular bases for this disorder [4], [5], [6], [7]. Up to date, more than 30 mtDNA mutations have been associated LHON worldwide [7]. Of these, the ND1 G3460A, ND4 G11778A, and ND6 T14484C mutations, in the genes encoding the subunits of respiratory chain complex I, are the most commonly LHON-associated mtDNA mutations, accounting for more than 50% of LHON pedigrees in different ethnic origins worldwide [2], [7], [8], [9], [10]. Typical features in LHON pedigrees are incomplete penetrance and male bias among the affected subjects, reflecting the complex etiology of this disease [11], [12]. These primary LHON-associated mtDNA mutations such as ND4 G11778A mutation by themselves are insufficient to produce a clinical phenotype. Therefore, other modifier factors including the nuclear modifier genes, mitochondrial haplotypes, and environmental factors modify the risk of optic neuropathy [12], [13].

With the aim of investigating the molecular basis of LHON in the Chinese population, a systematic and extended mutational screening of mtDNA has been initiated in the large clinical population of Ophthalmology Clinic at the Wenzhou Medical College, China [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. In the previous investigations, we showed that the LHON was associated with the ND4 G11778A mutation in 15 Chinese families with variable penetrance and severity and age-at-onset of visual impairment [11], [12], [13], [14], [15], [16]. Furthermore, ND6 T14484C mutation and ND1 G3460A mutation were identified in three Han Chinese families and one Chinese family, respectively [17], [18]. In addition, we showed that LHON is associated with the ND4 G11696A and ND1 T3394C mutations in Chinese families with extremely low penetrances of visual loss [19], [20]. In the present study, we performed the clinical, genetic, and molecular characterization of the other three Chinese families with suggestively maternally transmitted LHON. Molecular analysis has led to identification of the known T14502C mutation in ND6 gene in these Chinese families. To elucidate the role of mitochondrial haplotype in the phenotypic manifestation of the T14502C mutation, we performed a PCR-amplification of fragments spanning the entire mitochondrial genome and subsequent DNA sequence analysis in the matrilineal relatives of those Chinese families.

Section snippets

Materials and methods

Patients. As a part of genetic screening program for visual impairment, three Chinese families (Fig. 1) were ascertained through the School of Ophthalmology and Optometry, Wenzhou Medical College, and Ophthalmology Clinic, Beijing Dongfang Hospital, respectively. Informed consent, blood samples, and clinical evaluations were obtained from all participating family members, under protocols approved by the Cincinnati Children’s Hospital Medical Center Institute Review Board and the Wenzhou Medical

Clinical presentation

In family WZ401, the proband (III-1), as shown in Table 1, came to the Ophthalmology Clinic of Wenzhou Medical College at the age of 17 years. She began experiencing bilateral visual impairment at the age of 11 years. She saw a dark cloud in the center of her vision and had problems in appreciating colors, all of which seemed dark gray. Her visual acuity was 0.1 in both eyes. Visual field testing demonstrated large centrocecal scotomata in both eyes. Fundus examination showed that both of her

Discussion

In the present study, we have performed the clinical, genetic, and molecular characterization of three Chinese families with Leber’s hereditary optic neuropathy. The bilateral visual impairment as a sole clinical phenotype was only present in the maternal lineage of those pedigrees, suggesting that the mtDNA mutation is the molecular basis for this disorder. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to

Acknowledgments

M.X.G. was supported by National Institutes of Health (NIH) Grants RO1DC05230 and RO1DC07696 from the National Institute on Deafness and Other Communication Disorders. He is also grateful for the Chinese Young Scholar Award (30628013) received from National Science Foundation of China and for a key research Grant Z204492 received from Zhejiang Provincial Natural Science Foundation of China. J.Q. acknowledges a project Grant ZB0202 received from Zhejiang Provincial Natural Science Foundation of

References (34)

  • S. Zhang et al.

    T14484C and T14502C in the mitochondrial ND6 gene are associated with Leber’s hereditary optic neuropathy in a Chinese family

    Mitochondrion

    (2008)
  • T. Ozawa et al.

    Patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson’s disease and mitochondrial encephalomyopathy

    Biochem. Biophys. Res. Commun.

    (1991)
  • M.J. Bibb et al.

    Sequence and gene organization of mouse mitochondrial DNA

    Cell

    (1981)
  • W. Cai et al.

    Mitochondrial variants may influence the phenotypic manifestation of Leber’s hereditary optic neuropathy-associated ND4 G11778A mutation

    J. Genet. Genomics

    (2008)
  • N. Howell et al.

    Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy

    Am. J. Hum. Genet.

    (2003)
  • N.J. Newman

    Leber’s hereditary optic neuropathy

    Ophthalmol. Clin. North Am.

    (1993)
  • M.D. Brown et al.

    Phylogenetic analysis of Leber’s hereditary optic neuropathy mitochondrial DNA’s indicates multiple independent occurrences of the common mutations

    Hum. Mutat.

    (1995)
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