title: Human intellectual disability genes form conserved functional modules in Drosophila.
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.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Merel A W
authors.initials: MA
authors.lastname: Oortveld
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Keerthikumar
authors.forename: Martin
authors.initials: M
authors.lastname: Oti
authors.forename: Bonnie
authors.initials: B
authors.lastname: Nijhof
authors.forename: Ana Clara
authors.initials: AC
authors.lastname: Fernandes
authors.forename: Korinna
authors.initials: K
authors.lastname: Kochinke
authors.forename: Anna
authors.initials: A
authors.lastname: Castells-Nobau
authors.forename: Eva
authors.initials: E
authors.lastname: van Engelen
authors.forename: Thijs
authors.initials: T
authors.lastname: Ellenkamp
authors.forename: Lilian
authors.initials: L
authors.lastname: Eshuis
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Bianca
authors.initials: B
authors.lastname: Habermann
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.forename: Patrik
authors.initials: P
authors.lastname: Verstreken
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.forename: Annette
authors.initials: A
authors.lastname: Schenck
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D005123:Eye / Q000254:growth & development / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D034622:RNA Interference; D013569:Synapses / Q000235:genetics* / Q000378:metabolism