Human intellectual disability genes form conserved functional modules in Drosophila

PLoS Genet. 2013 Oct;9(10):e1003911. doi: 10.1371/journal.pgen.1003911. Epub 2013 Oct 31.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Drosophila / genetics
  • Eye / growth & development
  • Eye / metabolism*
  • Gene Knockdown Techniques
  • Genetic Variation
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism
  • Intellectual Disability / pathology
  • Metabolic Networks and Pathways / genetics*
  • Neurons / metabolism
  • Phenotype
  • RNA Interference
  • Synapses / genetics*
  • Synapses / metabolism

Grant support

This work was supported by the BioRange program of the Netherlands Bioinformatics Centre (NBIC http://www.nbic.nl/research, supported by Netherlands Genomics Initiative) to MO and HGB, by VIB, the research fund KU Leuven, an ERC Starting Grant (260678) and FWO grants to PV, by the European Union's FP7 large scale integrated network Gencodys (http://www.gencodys.eu/, HEALTH-241995) to HvB, MAH and AS, and by the German Mental Retardation Network funded by the NGFN+ program of the German Federal Ministry of Education and Research (BMBF), by an NCMLS/RUNMC fellowship, TOP (912-12-109), VIDI (917-96-346) and Aspasia grants from the Netherlands Organization for Scientific Research (NWO) to AS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.