在中國科學(xué)院“百人計(jì)劃”、國家杰出青年科學(xué)基金（30725044）資助下,，中國科學(xué)院昆明動(dòng)物研究所姚永剛課題組與中山大學(xué)中山眼科中心張清炯課題組通過合作研究,，發(fā)現(xiàn)特定線粒體DNA（mtDNA）單倍型類群對(duì)Leber遺傳性視神經(jīng)病變（簡(jiǎn)稱LHON）發(fā)病與否有重要影響，結(jié)果發(fā)表在生命科學(xué)領(lǐng)域國際頂尖雜志《美國人類遺傳學(xué)雜志》（The American Journal of Human Genetics）（2007年影響因子11.092）,。據(jù)悉,，這是迄今我國學(xué)者在有關(guān)LHON與mtDNA相關(guān)研究方面，首次在這類頂尖雜志上發(fā)表論文,。
LHON是導(dǎo)致青壯年突發(fā)雙目失明的最常見眼病,，也是最常見的線粒體基因遺傳病，由德國醫(yī)生Leber于1871年首先報(bào)告,。1988年美國Wallace研究組首先確定LHON的病因,，是由mtDNA突變所致，可以通過母親傳給全部后代,。在我國上世紀(jì)九十年代,，南京、福建和廣州的學(xué)者相繼發(fā)現(xiàn)我國LHON患者也是由mtDNA的幾個(gè)常見原發(fā)突變所致,。盡管LHON病因早已明確,，但發(fā)病機(jī)制仍有三大難題不明：為什么mtDNA突變攜帶者只有不到三分之一發(fā)病,？為什么男性發(fā)病率遠(yuǎn)遠(yuǎn)高于女性,？為什么mtDNA突變攜帶者要在青壯年發(fā)病,？這些有關(guān)發(fā)病風(fēng)險(xiǎn)問題的闡明,，是本病預(yù)防、早期干預(yù)及治療的關(guān)鍵,。遺憾的是,，國內(nèi)部分同行誤以為找到LHON的病因后就沒有多少值得研究的了,，并不支持基于這些關(guān)鍵問題的研究。
姚永剛課題組與張清炯課題組及其合作者首先從1600多個(gè)LHON家系中選擇有m.11778G>A原發(fā)突變的家系,，然后對(duì)175個(gè)有詳細(xì)家系資料的家系進(jìn)行了系統(tǒng)的分析,。通過分析每個(gè)家系mtDNA不同區(qū)域變異類型來確定該mtDNA所屬類群，結(jié)合每個(gè)家系中LHON發(fā)病情況進(jìn)行回歸分析,，發(fā)現(xiàn)線粒體單倍型類群M7b1’2顯著增加LHON的發(fā)病外顯率,，而單倍型類群M8a顯著降低發(fā)病率。在對(duì)歸屬于上述單倍型類群的患者線粒體全基因組序列進(jìn)行系統(tǒng)發(fā)育分析后發(fā)現(xiàn),，類群M7b1’2的致病性風(fēng)險(xiǎn)很可能是由于ND5基因上的類群特有性變異（m.12811T>C）和原發(fā)性突變之間存在的協(xié)同效應(yīng)引發(fā),；相反，類群M8a含有的位于ATPase6基因上的兩個(gè)類群特異性變異m.8584G>A和m.8684C>T很可能提供一種保護(hù)作用,，阻止原發(fā)突變m.11778G>A的外顯,，進(jìn)一步對(duì)含有這兩個(gè)M8a特有變異的ATPase6蛋白二級(jí)結(jié)構(gòu)變化的預(yù)測(cè)結(jié)果支持上述推測(cè)。該研究是目前東亞人群LHON病發(fā)情況和線粒體遺傳背景之間關(guān)系的首次系統(tǒng)性研究,，結(jié)果不僅對(duì)揭示mtDNA原發(fā)突變攜帶者LHON發(fā)病與否的相關(guān)危險(xiǎn)因素有重要價(jià)值,，而且為進(jìn)一步闡明LHON復(fù)雜的發(fā)病機(jī)制等后續(xù)研究提供了很好的思路和基礎(chǔ)，同時(shí)對(duì)國人LHON發(fā)病的遺傳咨詢和可能的早期干預(yù)提供了重要線索,。（生物谷Bioon.com）
生物谷推薦原始出處：
The American Journal of Human Genetics,，Volume 83, Issue 6, 760-768，Yanli Ji,，Yong-Gang Yao
Mitochondrial DNA Haplogroups M7b1′2 and M8a Affect Clinical Expression of Leber Hereditary Optic Neuropathy in Chinese Families with the m.11778G→A Mutation
Yanli Ji1, 6, A-Mei Zhang2, 4, 6, Xiaoyun Jia1, Ya-Ping Zhang3, Xueshan Xiao1, Shiqiang Li1, Xiangming Guo1, Hans-Jürgen Bandelt5, Qingjiong Zhang1, 6 and Yong-Gang Yao2, 6, ,
1 State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China
2 Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
3 State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
4 Graduate School of Chinese Academy of Sciences, Beijing 100039, China
5 Department of Mathematics, University of Hamburg, Hamburg 20146, Germany
6 These authors contributed equally to this work
Abstract
Leber hereditary optic neuropathy (LHON) is the most extensively studied mitochondrial disease, with the majority of the cases being caused by one of three primary mitochondrial DNA (mtDNA) mutations. Incomplete disease penetrance and gender bias are two features of LHON and indicate involvement of additional genetic or environmental factors in the pathogenesis of the disorder. Haplogroups J, K, and H have been shown to influence the clinical expression of LHON in subjects harboring primary mutations in European families. However, whether mtDNA haplogroups would affect the penetrance of LHON in East Asian families has not been evaluated yet. By studying the penetrance of LHON in 1859 individuals from 182 Chinese families (including one from Cambodia) with the m.11778G→A mutation, we found that haplogroup M7b1′2 significantly increases the risk of visual loss, whereas M8a has a protective effect. Analyses of the complete mtDNA sequences from LHON families with m.11778G→A narrow the association of disease expression to m.12811T→C (Y159H) in the NADH dehydrogenase 5 gene (MT-ND5) in haplogroup M7b1′2 and suggest that the specific combination of amino acid changes (A20T-T53I) in the ATP synthase 6 protein (MT-ATP6) caused by m.8584G→A and m.8684C→T might account for the beneficial background effect of M8a. Protein secondary-structure prediction for the MT-ATP6 with the two M8a-specific amino acid changes further supported our inferences. These findings will assist in further understanding the pathogenesis of LHON and guide future genetic counseling in East Asian patients with m.11778G→A.
