Abstract
Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.
Highlights
Intellectual Disability (ID) is defined by an IQ below 70, deficits in adaptive behavior and an onset before the age of 18
We systematically characterized behavioral and morphological phenotypes associated with 270 conserved ID genes, using the Drosophila eye and photoreceptor neurons as a model
Our findings provide unbiased evidence for the long suspected but never experimentally demonstrated functional coherence among ID disorders
Summary
Intellectual Disability (ID) is defined by an IQ below 70, deficits in adaptive behavior and an onset before the age of 18. Some ID genes appear to work together in specific pathways and processes, such as Rho GTPase pathways, MAP kinase signalling and synaptic plasticity [3,4] This has led to the suggestion that ID genes highlight key molecular networks that regulate human cognition [1,2,5,6,7]. Such networks are of wide interest for both fundamental neuroscience and translational medicine, and can pave the way for developing treatment strategies [2] Their identification is limited by the paucity of available information on the function of most ID genes. Model organisms such as the mouse have effectively been used as experimental systems to gain insights into ID gene function and neuropathology [8].
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