Deregulation of EIF4E: a novel mechanism for autism
Abstract
Background: Autism is a common childhood onset neurodevelopmental disorder, characterised by severe and sustained impairment of social interaction and social communication, as well as a notably restricted repertoire of activities and interests. Its aetiology is multifactorial with a strong genetic basis. EIF4E is the rate limiting component of eukaryotic translation initiation, and plays a key role in learning and memory through its control of translation within the synapse. EIF4E mediated translation is the final common process modulated by the mammalian target of rapamycin (mTOR), PTEN and fragile X mental retardation protein (FMRP) pathways, which are implicated in autism. Linkage of autism to the EIF4E region on chromosome 4q has been found in genome wide linkage studies. Methods and results: The authors present evidence that directly implicates EIF4E in autism. In a boy with classic autism, the authors observed a de novo chromosome translocation between 4q and 5q and mapped the breakpoint site to within a proposed alternative transcript of EIF4E. They then screened 120 autism families for mutations and found two unrelated families where in each case both autistic siblings and one of the parents harboured the same single nucleotide insertion at position −25 in the basal element of the EIF4E promoter. Electrophoretic mobility shift assays and reporter gene studies show that this mutation enhances binding of a nuclear factor and EIF4E promoter activity. Conclusions: These observations implicate EIF4E, and more specifically control of EIF4E activity, directly in autism. The findings raise the exciting possibility that pharmacological manipulation of EIF4E may provide therapeutic benefit for those with autism caused by disturbance of the converging pathways controlling EIF4E activity.
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NCKAP1 and eIF4E have been shown to be genetically associated with autism spectrum disorder.
“the two key CYFIP1 interactors examined here, NCKAP1 and eIF4E, have been shown to be genetically associated with ASD (Iossifov et al., 2012, Neves-Pereira et al., 2009).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Neves-Pereira et al., 2009
Dysregulation or mutations of FMRP-interacting proteins such as CYFIP1, eIF4E, and a subset of FMRP mRNA targets may contribute to the autism spectrum disorder phenotype observed in fragile X syndrome.
“Recent evidence indicates that dysregulation and or mutations of FMRP-interacting proteins, such as the cytoplasmic FMRP-interacting protein 1 (CYFIP1) (52-55), eukaryotic initiation factor 4 (eIF4E) (56,57), and a subset of FMRP mRNA targets (58), may contribute to the ASD phenotype observed in FXS.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [57]
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- Authors
- Neves-Pereira, M., Müller, B., Massie, D., Williams, J. H. G., O’Brien, P. C. M., Hughes, A., Shen, S.-B., Clair, D. S., & Miedzybrodzka, Z.
- Affiliations
- University of Aberdeen (GB)
- National Health Service (GB)
- University of Cambridge (GB)
- Corresponding author
- Miedzybrodzka, Z
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2009-06-25
- Volume
- 46
- Issue
- 11
- Pages
- 759-765
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- OpenAlex
- W2097231159
- Cited by
- 142
- References
- 42
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 10 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 14 · 2013: 19 · 2012: 13
- FWCI
- 5.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Manchester Biomedical Research Centre
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- eIF4E, autism spectrum disorder, chromosome 4q, single nucleotide insertion, nuclear factor binding, translation initiation, mTOR signaling, PTEN, FMRP, autism genetics, autism pharmacotherapy
- MeSH terms
- Autistic Disorder, Base Sequence, Brain, Cell Line, Child, Preschool, Chromosome Mapping, DNA Mutational Analysis, Gene Expression Regulation, HeLa Cells, Humans, Male, Molecular Sequence Data, Mutation, Pedigree, Promoter Regions, Genetic, RNA, Messenger, Translocation, Genetic, Mutagenesis, Insertional, Sequence Alignment, In Situ Hybridization, Fluorescence, Eukaryotic Initiation Factor-4E
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