Abstract
Chartier-Harlin and colleagues [2] recently reported mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene in families with parkinsonism. Large-scale screening found two mutations (p.R1205H and p.A502V) only in affected individuals, although their relative frequency was very low. The aim of this study was to investigate EIF4G1 parkinsonism-related variants in two separate cohorts and study coding variability across the gene. We first screened a series of familial Parkinson's Disease (PD) patients in an attempt to confirm previous results by showing segregation. Then, to determine the extent of coding variation in the gene, we first screened a cohort of sub-Saharan African individuals from the Centre d’Etude du Polymorphisme Humain – Human Genome Diversity Cell Line Panel (HGDP) [1] and then analyzed data from 5350 individuals National Heart, Lung, and Blood Institute (NHLBI) exome sequencing project. We failed to identify any PD-related mutations in the familial samples. Conversely we found the p.A502V variant in the NHLBI population. We observed a high number of coding polymorphism in the exons where the two PD variants have been previously reported. We conclude that either EIF4G1 variants are an extremely rare cause of familial PD in Caucasian cohorts, or that A502V is in fact a rare benign variant not involved in PD aetiology. Our data also suggests that the protein can tolerate some extent of variability particularly at this point of the gene.
Highlights
Contents lists available at SciVerse ScienceDirectArianna Tucci a,∗, Gavin Charlesworth a, Una-Marie Sheerin a, Vincent Plagnol b, Nicholas W
Chartier-Harlin and colleagues [2] recently reported mutations in the eukaryotic translation initiation factor 4-gamma (EIF4G1) gene in families with parkinsonism
We conclude that either EIF4G1 variants are an extremely rare cause of familial Parkinson’s Disease (PD) in Caucasian cohorts, or that A502V is a rare benign variant not involved in PD aetiology
Summary
Arianna Tucci a,∗, Gavin Charlesworth a, Una-Marie Sheerin a, Vincent Plagnol b, Nicholas W. Further molecular analysis of the EIF4G1 gene in a large case–control cohort (4500 cases and 3800 controls) identified another novel missense mutation (p.A502V) in three PD individuals, which was not found in controls. These data indicate that these variants are extremely rare in the PD population (0.2% for p.R1205H and 0.06% for p.A502V). Assignment of pathogenicity can be difficult when variants are very rare With this background, we screened 150 familial PD cases from our UK familial Parkinson’s Disease series, in which we have previously identified LRRK2, VPS35 and SNCA mutations [5,7] in order to determine. It has been observed in African-Americans (http://snp.gs.washington.edu/EVS), with a frequency of 0.15%
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