Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease
Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease
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DOI：
10.1016/j.ajhg.2011.08.009
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发表时间：
2011-09-09
影响因子：
9.8
通讯作者：
Farrer, Matthew J.
中科院分区：
文献类型：
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作者：
Chartier-Harlin, Marie-Christine;Dachsel, Justus C.;Farrer, Matthew J.
对一个常染色体显性帕金森综合征多发病家系的全基因组分析提示染色体3q 26-q28区域存在一个位点。真核生物翻译起始因子4-γ（EIF 4G 1）中的错义突变c.3614G>A（p.Arg1205His）解释了连锁和疾病分离。随后的序列和基因型分析鉴定了EIF 4G 1 c.1505C>T（p.Ala502Val）、c.2056G>T（p.Gly686Cys）、c.3490A>C（p.Ser1164Arg）、c.3589C>T（p.Arg1197Trp）和c.3614G>A（p.Arg1205His）在患有家族性帕金森综合征和特发性路易体病的受试者中的替换，但在对照受试者中没有。尽管来自不同的国家，但EIF 4G 1 c.1505C>T（p.Ala502Val）或c.3614G>A（p.Arg1205His）突变的人似乎与祖先的创始人共享单倍型。eIF 4G 1 p.Ala502Val和p.Arg1205His破坏eIF 4 E或eIF 3E结合，尽管野生型蛋白不破坏，并使突变细胞更容易受到反应性氧化物质的影响。EIF 4G 1突变涉及家族性帕金森综合征的mRNA翻译起始，并突出了单基因、毒素和可能病毒诱导的帕金森病的会聚途径。
Genome-wide analysis of a multi-incident family with autosomal-dominant parkinsonism has implicated a locus on chromosomal region 3q26-q28. Linkage and disease segregation is explained by a missense mutation c.3614G>A (p.Arg1205His) in eukaryotic translation initiation factor 4-gamma (EIF4G1). Subsequent sequence and genotype analysis identified EIF4G1 c.1505C>T (p.Ala502Val), c.2056G>T (p.Gly686Cys), c.3490A>C (p.Ser1164Arg), c.3589C>T (p.Arg1197Trp) and c.3614G>A (p.Arg1205His) substitutions in affected subjects with familial parkinsonism and idiopathic Lewy body disease but not in control subjects. Despite different countries of origin, persons with EIF4G1 c.1505C>T (p.Ala502Val) or c.3614G>A (p.Arg1205His) mutations appear to share haplotypes consistent with ancestral founders. eIF4G1 p.Ala502Val and p.Arg1205His disrupt eIF4E or eIF3E binding, although the wild-type protein does not, and render mutant cells more vulnerable to reactive oxidative species. EIF4G1 mutations implicate mRNA translation initiation in familial parkinsonism and highlight a convergent pathway for monogenic, toxin and perhaps virally-induced Parkinson disease.