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.
Bibliographical noteFunding Information:
We thank subjects who generously participated in this study. We also thank the many clinicians who have contributed to the follow-up of family P30 over the past 15 years, including Estelle Becquet, Serge Brique, Delphine Prince, Xavier Douay, and Nawal Waucquier. We acknowledge the laboratory support of Clotilde Levecque, Vincent Mouroux, Pierre Semaille, and Trevor Tyson. Studies in France would not have been possible without financial support from CHR de Lille, Université Lille 2, Inserm, French Ministry Hospital Clinical Research Programs (PHRCs) (1994/, 2002/1918, 2005/1914), Association France Parkinson (2005), Fondation de France 2004-013306, 2011-00016815, Fondation de la Recherche Médicale (2006), PPF (synucléothèque 2005-2009), the two Centres de Resources Biologiques (IPL-Lille, CHRU-Lille) and their scientific committee (A.D., M.-C.C.-H., Philippe Amouyel, Florence Pasquier, Régis Bordet). Studies in Ireland were supported by the Program for Research in Third Level Institutions (PRTLI). Studies in Italy were supported by the Italian Ministry of Health (Ricerca Corrente 2011, Ricerca Finalizzata, Giovani Ricercatori). Studies in the PROGENI sample were supported by R01NS37167 and the Parkinson Study Group. Clinicogenetic studies in Tunisia were funded in part by the Institute of Neurology, Tunis, and the Michael J. Fox Foundation. GlaxoSmithKline (GSK) funded and provided a subset of the Tunisian case:control samples and associated phenotypic data, and we gratefully acknowledge the PD Programme Team, most notably Tina Stapleton and Carole Stapleton for sample management. We thank James Weber and NIH National Heart, Lung, and Blood Institute/Marshfield Medical Research Foundation for genome-wide genotyping (genotyping award to M.J.F.). Studies performed at Mayo Clinic were financed by NIH National Institute of Neurological Disorders and Stroke (Morris K. Udall Parkinson's Disease Research Center of Excellence; P50 #NS40256 #NS072187; M.J.F., Z.K.W., D.W.D.), 2R01 ES10751 (D.M.M.), the Michael J. Fox Foundation (M.J.F.) and a Herb Geist gift for Lewy body research (M.J.F.). We thank Alice McKinney for supplementary Figure S3. This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (M.J.F.; C.V.-G.). In addition, Leading Edge Endowment Funds provided by the Province of British Columbia, Life Labs and Genome BC support the Dr. Donald Rix BC Leadership Chair (M.J.F.). The authors (J.O.A., D.W.D., M.J.F., D.M.M.) declare provisional patents relevant to Parkinson's disease, but not to EIF4G1. Royalties have been obtained from licensing related to alpha-synuclein (Alnylam Pharmaceuticals [M.J.F., D.M.M.], Isis Pharmaceuticals [M.J.F.]) and leucine-rich repeat kinase 2 (J.O.A., D.W.D., M.J.F., Z.K.W.) but no conflict of interest is declared.