A functional evidence for ATF۷IP association with human intellectual disabilities

Backgrounds: Intellectual disability (ID) is considered a multifactorial disorder with a highprevalence that compels considerable burdens on societies. A genome-wide association study(GWAS) on Iranian ID families reported an association of a novel genetic mutation inthe ATF۷IP gene. Although this demonstration has diagnostic importance, its functional roleneeds to be scrutinized. Drosophila melanogaster is a unique and well-known model organism toperform such functional investigations as its tiny brain resembles a high level of neurogeneticsand neurofunctional identities to the human brain.Materials and Methods: The Gal۴/UAS system is a highly applicable toolin Drosophila genetics that offers over-expression and/or silencing of a particular gene in a timeandtissue-specific manner. Therefore, the RNAi approach was employed to knock downthe wde gene, fly ortholog to ATF۷IP, in flies’ brain. Following confirmation of wde downregulation,its pathologic effects on the structure and function of neurons were assessed by brainmicroscopy and validated behavioural assays including olfactory conditioning, and courtshipconditioning learning and memories.Results: Based on huge functional similarities between the selected ATF۷IP gene and itsorthologs in Drosophila melanogaster, down-regulation of the wde gene led to neuronaldysfunction and induction of some sort of ID-like symptoms in flies.Conclusion: Since the transgenic Drosophila with brain-specific down-regulation for theselected gene display abnormalities in neuronal structure and functions, and memoryperformance then it can be considered as evidence for the statement on the association ofobserved genetic alterations and familial ID in the Iranian population.

کلیدواژه ها:

Intellectual disability ، ATF۷IP gene ، Functional assay ، Drosophila melanogaster ، wde gene