Dipartimento di Biologia Cellulare e Ambientale, Università di Perugia, Perugia, Italy.
PLoS One. 2012;7(8):e42242. doi: 10.1371/journal.pone.0042242. Epub 2012 Aug 3.
Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined.
METHODOLOGY/PRINCIPAL FINDINGS: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I.
CONCLUSIONS/SIGNIFICANCE: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.
Leber 遗传性视神经病变（LHON）是一种母系遗传的致盲性疾病，超过 90%的病例是由于三种主要线粒体 DNA（mtDNA）点突变（分别在 MT-ND4、MT-ND1 和 MT-ND6 基因中为 m.11778G>A、m.3460G>A 和 m.14484T>C）引起的。然而，导致其余 10%病例的 mtDNA 突变谱仅部分得到阐明，而且常常定义不明确。
方法/主要发现：为了改进这种病理性变异列表，我们对来自意大利、法国和德国的疑似 LHON 患者的线粒体基因组进行了完整测序，这些患者缺乏三种主要常见突变。进行了系统发育和保守性分析。发现 16 个线粒体基因组至少携带以下 9 种罕见 LHON 致病性突变中的一种：MT-ND1 基因中的 m.3700G>A/p.A132T、m.3733G>A-C/p.E143K-Q 和 m.4171C>A/p.L289M）、MT-ND4L（m.10663T>C/p.V65A）和 MT-ND6（m.14459G>A/p.A72V、m.14495A>G/p.M64I、m.14482C>A/p.L60S 和 m.14568C>T/p.G36S）。系统发育分析表明，这些取代是由于不同单倍群上的独立事件引起的，而种间比较表明，它们影响了 I 复合物 ND 亚单位基因中的保守氨基酸残基或结构域。
结论/意义：我们的研究结果表明，这 9 个取代都是原发性 LHON 突变。因此，尽管它们的频率相对较低，但在缺乏三种常见突变的所有 LHON 患者中都应常规检测这些突变。此外，我们的序列分析证实了单倍群 J1c 和 J2b（在我们的患者中超过 35%，而在西欧一般人群中为 6%）以及其他潜在协同性 mtDNA 变异在 LHON 表达中的主要作用。
