Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.
Haplotype and phylogenetic analyses suggest that one European-specific mtDNA background plays a role in the expression of Leber hereditary optic neuropathy by increasing the penetrance of the primary mutations 11778 and 14484.
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发表时间：
1997-05
影响因子：
9.8
通讯作者：
A. Torroni;Maurizio Petrozzi;L. D'urbano;D. Sellitto;M. Zeviani;Franco;Carrara;C. Carducci
中科院分区：
文献类型：
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作者：
A. Torroni;Maurizio Petrozzi;L. D'urbano;D. Sellitto;M. Zeviani;Franco;Carrara;C. Carducci
对来自37名患有Leber遗传性视神经病变（LHON）的意大利受试者（28名为11778阳性，7名为3460阳性，2名为14484阳性）和来自99名意大利对照者的mtDNAs进行了筛选，以检测目前与LHON相关的大多数突变。高分辨率限制性内切酶分析也进行了所有的科目，以确定患者和对照组中观察到的mtDNA单倍型和LHON突变之间的系统发育关系。该分析表明，推定的次级/中间LHON突变4216、4917、13708、15257和15812是古老的多态性，与特定组合相关，并定义了两个常见的高加索人种特异性单倍型分组（单倍型群J和T）。相反，相同的分析表明，原发突变11778、3460和14484是最近发生的，并且是由于多次突变事件。然而，系统发育分析也揭示了三个主要突变的不同进化模式。这3460个突变沿着系统发育树随机分布，与9个单倍群没有任何优先关联（H，I，J，K，T，U，V，W和X），而11778和14484突变显示出与单倍群J的强烈优先关联。这一发现表明，单倍群J-特异性突变增加了两个主要突变11778和14484的突变率和疾病表达的风险。
mtDNAs from 37 Italian subjects affected by Leber hereditary optic neuropathy (LHON) (28 were 11778 positive, 7 were 3460 positive, and 2 were 14484 positive) and from 99 Italian controls were screened for most of the mutations that currently are associated with LHON. High-resolution restriction-endonuclease analysis also was performed on all subjects, in order to define the phylogenetic relationships between the mtDNA haplotypes and the LHON mutations observed in patients and in controls. This analysis shows that the putative secondary/intermediate LHON mutations 4216, 4917, 13708, 15257, and 15812 are ancient polymorphisms, are associated in specific combinations, and define two common Caucasoid-specific haplotype groupings (haplogroups J and T). On the contrary, the same analysis shows that the primary mutations 11778, 3460, and 14484 are recent and are due to multiple mutational events. However, phylogenetic analysis also reveals a different evolutionary pattern for the three primary mutations. The 3460 mutations are distributed randomly along the phylogenetic trees, without any preferential association with the nine haplogroups (H, I, J, K, T, U, V, W, and X) that characterize European populations, whereas the 11778 and 14484 mutations show a strong preferential association with haplogroup J. This finding suggests that one ancient combination of haplogroup J-specific mutations increases both the penetrance of the two primary mutations 11778 and 14484 and the risk of disease expression.