Dataset Information

Translation initiator EIF4G1 mutations in familial Parkinson disease.

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.

SUBMITTER: Chartier-Harlin MC

PROVIDER: S-EPMC3169825 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Translation initiator EIF4G1 mutations in familial Parkinson disease.

Chartier-Harlin Marie-Christine MC Dachsel Justus C JC Vilariño-Güell Carles C Lincoln Sarah J SJ Leprêtre Frédéric F Hulihan Mary M MM Kachergus Jennifer J Milnerwood Austen J AJ Tapia Lucia L Song Mee-Sook MS Le Rhun Emilie E Mutez Eugénie E Larvor Lydie L Duflot Aurélie A Vanbesien-Mailliot Christel C Kreisler Alexandre A Ross Owen A OA Nishioka Kenya K Soto-Ortolaza Alexandra I AI Cobb Stephanie A SA Melrose Heather L HL Behrouz Bahareh B Keeling Brett H BH Bacon Justin A JA Hentati Emna E Williams Lindsey L Yanagiya Akiko A Sonenberg Nahum N Lockhart Paul J PJ Zubair Abba C AC Uitti Ryan J RJ Aasly Jan O JO Krygowska-Wajs Anna A Opala Grzegorz G Wszolek Zbigniew K ZK Frigerio Roberta R Maraganore Demetrius M DM Gosal David D Lynch Tim T Hutchinson Michael M Bentivoglio Anna Rita AR Valente Enza Maria EM Nichols William C WC Pankratz Nathan N Foroud Tatiana T Gibson Rachel A RA Hentati Faycal F Dickson Dennis W DW Destée Alain A Farrer Matthew J MJ

American journal of human genetics 20110901 3

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 i ...[more]

PMID: 21907011

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Project description:IMPORTANCE:Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE:To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS:A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES:Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS:The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE:TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD.

Dataset Information

Translation initiator EIF4G1 mutations in familial Parkinson disease.

Publications

Translation initiator EIF4G1 mutations in familial Parkinson disease.

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