Abstract
EIF4G1 mutations were previously reported as a cause of PD. As a result of this finding considerable work has been performed to test this idea and to examine the functional role of eukaryotic translation initiation factor 4-gamma in the pathogenic process underlying PD. Here we show that the originally described mutation is likely a rare benign variant. We tested this variant in a very large series of subjects and show that it is more frequent in controls than cases. We argue here that this infers that EIF4G1 mutations are not related to PD.
In 2011 the gene encoding eukaryotic translation initiation factor 4-gamma (EIF4G1) was suggested to contain mutations that cause autosomal dominant Parkinson’s disease, often with dementia (Chartier-Harlin et al. 2011, 1). The authors performed genome-wide linkage analysis of a multi-incident northern French family with autosomal-dominant late-onset parkinsonism, the result of which indicated a disease segregating mutation at 3q26-q28. Following positional sequencing the authors identified a segregating mutation in EIF4G1, p.R1205H (rs112176450). On the basis of this mutation subsequent screening of a cohort of PD patients was performed. This revealed additional mutations in PD cases that were absent from controls, p.A502V, p.G686C, p.S1164R, and p.R1197W.
Following this report several groups have screened this gene, but to date no group has provided strongly supportive evidence for the involvement of EIF4G1 mutations in PD (Siitonen et al. 2013, 1; Huttenlocher et al. 2014, 1; Blanckenberg et al. 2014, 1; Chen et al. 2013, 1; Fujioka et al. 2013, 144; Nishioka et al. 2014, 1; Lesage et al. 2012; Tucci et al. 2012). While these reports have failed to provide support, the absence of evidence is not the evidence of absence, and thus the role of EIF4G1 mutations in PD has remained unclear.
We designed the genotyping array NeuroX to include variants related to neurological disease, including risk variants identified by genome wide association studies and mutations implicated as disease causing. The NeuroX content includes several of the originally reported EIF4G1 mutations, including the principle disease segregating p.R1205H mutation on which the nomination of EIF4G1 as a PD gene rests. We have assayed 6,249 PD subjects and 6,032 controls using NeuroX (Nalls et al. 2014).
These data revealed an excess of p.R1205H heterozygotes in controls compared to cases, being present in 5 of 6,032 controls, and only in 1 of 6,249 cases. Cluster plots for the genotyping of this variant revealed apparently high quality genotyping (figure 1). Because this was the originally identified mutation, which led to the screening of other cases for EIF4G1 mutations, we believe these data strongly suggest that this is not a gene for PD, and that this variant is a rare benign polymorphism.
Figure 1.
Cluster plots from NeuroX for the 3 EIF4G1 mutations. These plots were generated from log R Ratio and B Allele Frequency exported from Genome Studio (Illumina, Inc) and plotted in R.
We also had data available for two other variants that had previously been described as mutations, p.A502V (rs111290936) and p.R1197W (rs113388242). We identified one p.A502V heterozygote in 6,032 controls and five in 6,249 cases. We failed to identify any cases with the p.R1197W variant, but did find a single heterozygous control.
We confirmed each of these changes using Sanger sequencing in available DNA samples (figure 2).
Figure 2.
Representative chromatograms from Sanger sequencing for each of the 3 mutations. For each mutation a heterozygous sample is shown above, with a homozygous wild type shown below. The variant of interest is highlighted in each case.
These data argue convincingly that the mutation p.R1205H is not a cause of PD. Because this mutation was the underlying rationale for nominating EIF4G1 mutations as a cause of PD we believe the consequence of this finding is that EIF4G1 mutations are not a cause of PD. Given the investment in understanding the pathogenic role of the protein product of EIF4G1 in the pathobiology of PD it is important to correct the belief that this is a PD associated gene (Dhungel et al. 2014). These data also highlight the utility of NeuroX in screening large sample series for mutations.
Supplementary Material
Table.
Distribution of cases and controls with identified EIF4G1 mutations.
| Cases (n=6249) | Controls (n=6032) | |||||
|---|---|---|---|---|---|---|
| n | Origin | Age at Onset |
n | Origin | Age | |
|
p.R1205H (rs112176450) |
1 | North American | 60 | 5 | North American North American North American European WUSTL_903 |
78 76 75 68 68 |
|
p.R1197W (rs113388242) |
0 | - | - | 1 | Greek* | 46 |
|
p.A502V (rs111290936) |
5 | North American North American French North American** German |
71 61 64 76 73 |
1 | North American | 77 |
previously reported in (Lesage et al. 2012)
PD by self-report
Highlights.
EIF4G1 mutations were previously reported as a cause of Parkinson’s disease
We show here that the originally reported mutation is present in controls more often than in cases
These data argue that EIF4G1 mutations are not a cause of Parkinson’s disease
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- Blanckenberg Janine, Ntsapi Claudia, Carr Jonathan A, Bardien Soraya. EIF4G1 R1205H and VPS35 D620N Mutations Are Rare in Parkinson’s Disease from South Africa. Neurobiology of Aging. 2014;35(2):445. doi: 10.1016/j.neurobiolaging.2013.08.023. e1-3. [DOI] [PubMed] [Google Scholar]
- Chartier-Harlin Marie-Christine, Dachsel Justus C, Vilariño-Güell Carles, Lincoln Sarah J, Leprêtre Frédéric, Hulihan Mary M, Kachergus Jennifer, et al. Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease. American Journal of Human Genetics. 2011;89(3):398–406. doi: 10.1016/j.ajhg.2011.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chen YongPing, Chen Ke, Song Wei, Chen XuePing, Cao Bei, Huang Rui, Zhao Bi, et al. VPS35 Asp620Asn and EIF4G1 Arg1205His Mutations Are Rare in Parkinson Disease from Southwest China. Neurobiology of Aging. 2013;34(6):1709. doi: 10.1016/j.neurobiolaging.2012.11.003. e7-8. [DOI] [PubMed] [Google Scholar]
- Dhungel Nripesh, Eleuteri Simona, Li Ling-Bo, Kramer Nicholas J, Chartron Justin W, Spencer Brian, Kosberg Kori, et al. Parkinson’s Disease Genes VPS35 and EIF4G1 Interact Genetically and Converge on A-Synuclein. Neuron. 2014 Dec; doi: 10.1016/j.neuron.2014.11.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fujioka Shinsuke, Sundal Christina, Strongosky Audrey J, Castanedes Monica Case, Rademakers Rosa, Ross Owen A, Vilariño-Güell Carles, Farrer Matthew J, Wszolek Zbigniew K, Dickson Dennis W. Sequence Variants in Eukaryotic Translation Initiation Factor 4-Gamma (eIF4G1) Are Associated with Lewy Body Dementia. Acta Neuropathologica. 2013;125(3):425–438. doi: 10.1007/s00401-012-1059-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huttenlocher Johanna, Krüger Rejko, Capetian Philipp, Lohmann Katja, Brockmann Kathrin, Csoti Ilona, Klein Christine, et al. EIF4G1 Is Neither a Strong nor a Common Risk Factor for Parkinson’s Disease: Evidence from Large European Cohorts. Journal of Medical Genetics. 2014 Nov; doi: 10.1136/jmedgenet-2014-102570. [DOI] [PubMed] [Google Scholar]
- Lesage Suzanne, Condroyer Christel, Klebe Stephan, Lohmann Ebba, Durif Franck, Damier Philippe, Tison François, et al. EIF4G1 in Familial Parkinson’s Disease: Pathogenic Mutations or Rare Benign Variants? Neurobiology of Aging. 2012;33(9):2233. doi: 10.1016/j.neurobiolaging.2012.05.006. e1-2233.e5. [DOI] [PubMed] [Google Scholar]
- Nalls Mike A, Pankratz Nathan, Lill Christina M, Do Chuong B, Hernandez Dena G, Saad Mohamad, DeStefano Anita L, et al. Large-Scale Meta-Analysis of Genome-Wide Association Data Identifies Six New Risk Loci for Parkinson’s Disease. Nature Genetics. 2014;46(9):989–993. doi: 10.1038/ng.3043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nishioka Kenya, Funayama Manabu, Vilariño-Güell Carles, Ogaki Kotaro, Li Yuanzhe, Sasaki Ryogen, Kokubo Yasumasa, et al. EIF4G1 Gene Mutations Are Not a Common Cause of Parkinson’s Disease in the Japanese Population. Parkinsonism & Related Disorders. 2014;20(6):659–661. doi: 10.1016/j.parkreldis.2014.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Siitonen A, Majounie E, Federoff M, Ding J, Majamaa K, Singleton AB. Mutations in EIF4G1 Are Not a Common Cause of Parkinson’s Disease. European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies. 2013;20(4):e59. doi: 10.1111/ene.12051. [DOI] [PubMed] [Google Scholar]
- Tucci Arianna, Charlesworth Gavin, Sheerin Una-Marie, Plagnol Vincent, Wood Nicholas W, Hardy John. Study of the Genetic Variability in a Parkinson’s Disease Gene: EIF4G1. Neuroscience Letters. 2012;518(1):19–22. doi: 10.1016/j.neulet.2012.04.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.