Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

• Published in: American journal of human genetics Vol. 89; no. 3; pp. 398 - 406
• Main 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., Frigerio, Roberta, Maraganore, Demetrius M., Gosal, David, Lynch, Tim, Hutchinson, Michael, Bentivoglio, Anna Rita, Valente, Enza Maria, Nichols, William C., Pankratz, Nathan, Foroud, Tatiana, Gibson, Rachel A., Hentati, Faycal, Dickson, Dennis W., Destée, Alain, Farrer, Matthew J.
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 09.09.2011; Cell Press; Elsevier
• Subjects: Base Sequence; Binding sites; Biological and medical sciences; Chromosomes; Chromosomes, Human, Pair 3 - genetics; Cloning, Molecular; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Copy Number Variations; DNA Mutational Analysis; Eukaryotic Initiation Factor-4G - genetics; Flow Cytometry; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Linkage; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Genotype & phenotype; Humans; Immunoprecipitation; Medical genetics; Medical sciences; Mitochondria - physiology; Molecular and cellular biology; Molecular Sequence Data; Mutation; Mutation, Missense - genetics; Neurology; Parkinson Disease - genetics; Parkinson's disease; Pedigree; Protein Biosynthesis - genetics; Proteins; Human; Nervous system diseases; Familial disease; Initiator; Central nervous system disease; Parkinson disease; Genetics; Degenerative disease; Mutation; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2011.08.009

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.