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Translation initiator EIF4G1 mutations in familial Parkinson disease

Authors:	Chartier-Harlin Marie-Christine Dachsel Justus C Vilariño-Güell Carles Lincoln Sarah J Leprêtre Frédéric Hulihan Mary M Kachergus Jennifer Milnerwood Austen J Tapia Lucia Song Mee-Sook Le Rhun Emilie Mutez Eugénie Larvor Lydie Duflot Aurélie Vanbesien-Mailliot Christel Kreisler Alexandre Ross Owen A Nishioka Kenya Soto-Ortolaza Alexandra I Cobb Stephanie A Melrose Heather L Behrouz Bahareh Keeling Brett H Bacon Justin A Hentati Emna Williams Lindsey Yanagiya Akiko Sonenberg Nahum Lockhart Paul J Zubair Abba C Uitti Ryan J Aasly Jan O Krygowska-Wajs Anna Opala Grzegorz Wszolek Zbigniew K

Affiliation:	¹Université Lille Nord de France, F-59000 Lille, France;²Institut National de la Santé et de la Recherche Médicale (Inserm) UMR837, Institut de Recherches sur le Cancer de Lille (IRCL), Place de Verdun, 59045 Lille Cedex, IFR114 IMPRT F-59000 Lille, France;³Departments of Neurology and Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA;⁴Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada;⁵Centre Hospitalier Régional Universitaire de Lille(CHRU), Department of Neurology and Movement Disorders, F-59000 Lille, France;⁶Université des Sciences et Technologies de Lille (USTL), Department of Neurosciences, Villeneuve d'Ascq, F-59655 France;⁷Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 3R1, Canada;⁸Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Parkville, Victoria 3052, Australia;⁹Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL 32224, USA;¹⁰Department of Neurology, St. Olav's Hospital, Trondheim N-7006, Norway;¹¹Department of Neurology, Collegium Medicum, Jagiellonian University, Krakow 31-358, Poland;¹²Department of Neurology, Aging, Degenerative and Cerebrovascular Disorders, Medical University of Silesia, Katowice 40-055, Poland;¹³Department of Neurology, Mayo Clinic, Rochester, MN 55909, USA;¹⁴Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin 7, Ireland;¹⁵Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland;¹⁶Department of Neurology, St Vincent's University Hospital, Dublin 4, Ireland;¹⁷Institute of Neurology, Catholic University, Rome 00168, Italy;¹⁸Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Italy;¹⁹Department of Medical and Surgical Pediatric Sciences, University of Messina, Messina, 98124 Italy;²⁰Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA;²¹Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;²²GlaxoSmithKline Pharmaceuticals, Research and Development, Harlow, Greenford, Hammersmith CM19 5AW, UK;²³Service de Neurologie, Institut National de Neurologie, 1007 La Rabta, Tunis, Tunisia

Abstract:	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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