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Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

2011; Elsevier BV; Volume: 89; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2011.08.009

1537-6605

Marie‐Christine Chartier‐Harlin, Justus C. Dächsel, Carles Vilariño‐Güell, Sarah Lincoln, Frédéric Leprêtre, Mary Hulihan, Jennifer M. Kachergus, Austen J. Milnerwood, Lucı́a Tapia, Mee-Sook Song, Émilie Le Rhun, Eugénie Mutez, Lydie Larvor, Aurélie Duflot, Christel Vanbesien-Mailliot, Alexandre Kreisler, Owen A. Ross, Kenya Nishioka, Alexandra I. Soto‐Ortolaza, Stephanie A. Cobb, Heather L. Melrose, Bahareh Behrouz, Brett H. Keeling, Justin A. Bacon, Emna Hentati, Lindsey N. Williams, Akiko Yanagiya, Nahum Sonenberg, Paul J. Lockhart, Abba C. Zubair, Ryan J. Uitti, Jan Aasly, Anna Krygowska‐Wajs, Grzegorz Opala, Zbigniew K. Wszołek, Roberta Frigerio, Demetrius M. Maraganore, David Gosal, Tim Lynch, Michael Hutchinson, Anna Rita Bentivoglio, Enza Maria Valente, William C. Nichols, Nathan Pankratz, Tatiana Foroud, Rachel A. Gibson, Fayçal Hentati, Dennis W. Dickson, A. Destée, Matthew J. Farrer,

Nuclear Receptors and Signaling

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.