Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 89, Issue 3, Pages 398-406Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2011.08.009
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Funding
- CHR de Lille, Universite Lille 2, Inserm, French Ministry [1994/, 2002/1918, 2005/1914]
- Association France Parkinson
- Fondation de France [2004-013306, 2011-00016815]
- Fondation de la Recherche Medicate
- Program for Research in Third Level Institutions (PRTLI)
- Italian Ministry of Health
- Parkinson Study Group
- Institute of Neurology, Tunis
- Michael J. Fox Foundation
- GlaxoSmithKline (GSK)
- NIH National Institute of Neurological Disorders and Stroke [NS40256, NS072187, 2R01 ES10751]
- Canada Excellence Research Chairs program
- [R01NS37167]
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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.
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