Sudoyo Herawati, Suryadi Helena, Lertrit Patcharee, Pramoonjago Patcharin, Lyrawati Diana, Marzuki Sangkot
Eijkman Institute for Molecular Biology, Jl. Diponegoro 69, Jakarta 10430, Indonesia.
J Hum Genet. 2002;47(11):594-604. doi: 10.1007/s100380200091.
We studied 19 patients of Southeast Asian (SEA) ethnic ancestry with Leber's hereditary optic neuropathy (LHON) to investigate the mtDNA haplotypes associated with the primary mutation(s). Eighteen patients carried a mitochondrial DNA (mtDNA) G11778A mutation (Arg340His in the respiratory complex I ND4 subunit), while one had a T14484C mutation (Met64Val in the ND6 subunit). One patient had a class II LHON mtDNA mutation, G3316A. Sequencing data of the ND genes showed many single-nucleotide polymorphisms (62 SNPs in 17 individuals; 10 LHON patients and 7 normal controls) not previously reported in Europeans or Japanese. The SEA G11778A LHON mutation was associated mostly with two mtDNA haplogroups, M (47%) and a novel lineage, characterized by the gain of a 10394 DdeI site but absence of the 10397 AluI site, designated BM (37%). A significant association was observed between one SNP, A10398G, resulting in a Thr114Ala substitution in the ND3 subunit, and the primary LHON mutation. This SNP also characterizes haplogroup J, with which the European LHON 11778 and 14484 mutations show preferential association. The combination of A10398G and other SNPs, specific for the haplogroups J, M, or BM, might act synergistically to increase the penetrance of the LHON mutations, thus allowing their detection.
我们研究了19名具有东南亚（SEA）种族血统的Leber遗传性视神经病变（LHON）患者，以调查与原发性突变相关的线粒体DNA（mtDNA）单倍型。18名患者携带线粒体DNA（mtDNA）G11778A突变（呼吸链复合体I ND4亚基中的Arg340His），而1名患者有T14484C突变（ND6亚基中的Met64Val）。1名患者有II类LHON mtDNA突变，G3316A。ND基因的测序数据显示了许多单核苷酸多态性（17名个体中有62个单核苷酸多态性；10名LHON患者和7名正常对照），这些多态性在欧洲人或日本人中未曾报道过。SEA G11778A LHON突变主要与两个mtDNA单倍群相关，M（47%）和一个新的谱系，其特征是获得了一个10394 DdeI位点但没有10397 AluI位点，命名为BM（37%）。观察到一个单核苷酸多态性A10398G（导致ND3亚基中的Thr114Ala替代）与原发性LHON突变之间存在显著关联。该单核苷酸多态性也是单倍群J的特征，欧洲LHON 11778和14484突变与单倍群J优先相关。A10398G与单倍群J、M或BM特有的其他单核苷酸多态性的组合可能协同作用以增加LHON突变的外显率，从而使其得以检测。
