Deregulation of EIF4E

a novel mechanism for autism

M Neves-Pereira, B Muller, D Massie, J H G Williams, P C M O'Brien, A Hughes, S-B Shen, David St Clair, Z Miedzybrodzka

Research output: Contribution to journalArticle

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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 225 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.

Original languageEnglish
Pages (from-to)759-765
Number of pages7
JournalJournal of Medical Genetics
Volume46
Issue number11
Early online date25 Jun 2009
DOIs
Publication statusPublished - Nov 2009

Keywords

  • initiation-factor 4E
  • translation initiation
  • synaptic plasticity
  • spectrum disorders
  • dependent translation
  • protein-synthesis
  • messenger-RNA
  • white-matter
  • gene
  • individuals

Cite this

Deregulation of EIF4E : a novel mechanism for autism. / Neves-Pereira, M; Muller, B; Massie, D; Williams, J H G; O'Brien, P C M; Hughes, A; Shen, S-B; St Clair, David; Miedzybrodzka, Z.

In: Journal of Medical Genetics, Vol. 46, No. 11, 11.2009, p. 759-765.

Research output: Contribution to journalArticle

Neves-Pereira, M ; Muller, B ; Massie, D ; Williams, J H G ; O'Brien, P C M ; Hughes, A ; Shen, S-B ; St Clair, David ; Miedzybrodzka, Z. / Deregulation of EIF4E : a novel mechanism for autism. In: Journal of Medical Genetics. 2009 ; Vol. 46, No. 11. pp. 759-765.
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AU - Muller, B

AU - Massie, D

AU - Williams, J H G

AU - O'Brien, P C M

AU - Hughes, A

AU - Shen, S-B

AU - St Clair, David

AU - Miedzybrodzka, Z

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N2 - 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 225 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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KW - synaptic plasticity

KW - spectrum disorders

KW - dependent translation

KW - protein-synthesis

KW - messenger-RNA

KW - white-matter

KW - gene

KW - individuals

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