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Pathogenicity of homoplasmic mitochondrial DNA mutation and nuclear gene involvement
  1. Institute of Clinical Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba City, 305-8575 Japan

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    Editor—Seneca et al 1 reported a homoplasmic deletion of a T nucleotide in a 5T stretch (15 940-15 944 base pairs (bp)) of mitochondrial DNA (mtDNA) in two families associated with clinical and pathological findings of mt cytopathy. Although this deletion was homoplasmic and did not fulfil the classical criteria of pathological mutation, Seneca et al 1suggested that it was pathological, as they could not identify any other heteroplasmic mutations, deletions, or duplications in tRNA genes of mtDNA in these patients. However, this mutation was present not only in affected patients but also in asymptomatic relatives in both families. Therefore, this mutation does not cosegregate with the disease. It is difficult to confirm whether homoplasmic mutations are pathological, as was recently indicated by Chinneryet al.2 3 There are currently no concrete criteria to determine what kind of homoplasmic mtDNA abnormalities are pathological. Maternal inheritance is an important characteristic to confirm their pathogenicity, which, however, was not significant in these two families. The mode of inheritance of this deletion is difficult to confirm, as it is currently unknown whether the single nucleotide deletion is inherited maternally like mtDNA point mutations. It is possible that it is inherited autosomal dominantly like mtDNA deletions.4 In such cases, cosegregation of the mutation in affected family members is important to determine its pathogenicity. A population based association study is another method for confirming a significant role of homoplasmic or heteroplasmic mtDNA mutations. The association should also be confirmed by other studies on the same and different ethnic groups.

    By directly sequencing a mutation hot spot of mtDNA (3130-3423 bp) from 30 patients with type 2 diabetes mellitus (DM), we identified a G3316A homoplasmic mutation.5 The prevalence of this mutation was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance.5 This missense mutation in the ND-1 gene, which substitutes alanine for threonine, was present at an increased frequency in patients with type 2 DM compared with non-diabetic subjects in other studies in Japanese6 or European7 populations. The same mutation was also identified in a patient through screening patients with hypertrophic cardiomyopathy, suggesting a role of this homoplasmic mutation in the development of mt cytopathy (manuscript in preparation). Although homoplasmic mtDNA mutations do not fulfil the classical criteria for pathogenicity, another recent study indicated that homoplasmic mutations are significantly associated with type 2 DM (p=0.0011, 0.0457, 0.0194).8 These findings suggest that the homoplasmic mutations are also of pathological importance in mt cytopathy. Investigations on Leber's hereditary optic neuropathy (LHON) suggest a role of the nuclear gene in the pathogenesis of clinical symptoms of mt cytopathy. Previous investigations, however, failed to identify any nuclear gene abnormalities in patients with mt cytopathy.9 We consider that homoplasmic mutations are also important in the development of mt cytopathy, as nuclear DNA may be involved in its pathogenesis.

    Concerning the A3243G mutation, we suspect that nuclear gene abnormalities may be responsible for the different clinical phenotypes of type 2 DM or MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) associated with the same A3243G mutation.10 Recent investigations indicate that nuclear encoded gene mutations are associated with Leigh syndrome.11 12 These observations highlight the importance of nuclear gene-mtDNA interaction in the pathogenesis of mt dysfunction. They also suggest that homoplasmic mtDNA mutations are important in developing mt cytopathy, such as mt myopathies, diabetes mellitus, or cardiomyopathies. Although difficulties exist in confirming a pathogenic role of homoplasmic mtDNA mutations, some homoplasmic mutations are probably associated with mt dysfunction causing mt cytopathy. We propose that investigations of mtDNA abnormalities in patients with mt dysfunction should include homoplasmic mutations which cosegregate with clinical or pathological manifestations of mt cytopathy or are present with an increased frequency in affected patients.


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      S Seneca W Lissens I Liebaers P van den Bergh M C Nassogne A Benatar L de Meirleir