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Title: A Gene for Autism Identified by Translocation Breakpoint Mapping
Author: Neves Pereira, Maria de Lurdes Marques
ISNI:       0000 0001 3442 5822
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2008
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Autistic disorder (AD). is a common form of childhood neurodevelopmental disorder, characterized by severe and sustained impairment of social interaction and social communicative abilities, as well as a markedly restricted repertoire of activities and interests (American Psychiatric Association, 1994). Microscopic chromosomal rearrangements are seen in 3-6% of cases. Submicroscopic copy number variations (CNVs) were recently.identified in 10% patients with sporadic autism. Intriguingly, these were only found in 2% of patients with an affected first-degree relative, and in 1.0% of controls. Similar findings were reported by the Autism consortium, suggesting that single gene defects are more likely to be causative where autism is familial. We have used molecular analysis of a de:110vo balanced translocation in a case of classic autism independently to implicate the mRNA cap binding translation initiation factor EIF4E, already a strong positional candidate in autism. A de novo apparently balanced reciprocal translocation between the long arms of chromosomes 4 and 5 (46,XY,t(4:5)(q23;q31.3)) was identified in a child with classic AD. Linkage has been reported in autistic families to EIF4E region on chromosome 4, but not to the NR3C1 region on chromosome five. We thus sequenced the EIF4E promoter, and its seven exons in 120 multi-case families from the Autism Genetic Research Exchange collection (AGRE; base C insertion was identified within the previously identified 12 base pair critical region of the EIF4E promoter in a parent and both affected siblings from two different families. Electrophoretic mobility shift assays (EMSA) demonstrated that this promoter variant had an increased affinity for a nuclear factor, presumably hn-RNPK and when tested in a promoter activity assay using luciferase as reporter gene demonstrated a higher increase in EIF4E promoter activity in the presence of the single base insertion. Expression analysis failed to identify a significant difference in levels of EIF4E in transformed lymphocyte cell lines in either the translocation case or the cases with the promoter variant, indicating that subtle changes in EIF4E expression, perhaps occurring only in the brain/ nervous system/neurons may be sufficient to affect function. EIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs, to initiate protein synthesis. In molecular pathology, EIF4E is best known for its role as an oncogene, but it has been recently recognized to be important in memory because of its key role in mediating synaptic plasticity through translation initiation. Other molecules that interact with EIF4E or modulate its activity have been implicated in the control of translation initiation and synaptic plasticity, and also in the pathogenesis of autism. Yonan and co-workers showed linkage to the EIF4E region as part of a large genome wide scan of AGRE families, and suggested this gene as one of many positional candidates. Linkage to 4q21-31 has been confirmed in two other analyses of the AGRE cohort. We now:provide dire.ct evidence for a role of EIF4E in autism. Genetically determined up-regulation of synaptic translation is associated with autistic features in humans, and mice. In Fragile X, a severe learning disability syndrome frequently associated autistic features, synaptic mRNA translation is up-regulated through inactivation of the protein FMRP, causing an increase in the number of dendritic spines present on cortical neurons. EIF4E is the rate limiting component of eukaryotic translation, and thus is fundamental to the process of LTP.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available