Human intellectual disability genes form conserved functional modules in Drosophila.
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 inte...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-10-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3814316?pdf=render |
| _version_ | 1811230156779421696 |
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| author | Merel A W Oortveld Shivakumar Keerthikumar Martin Oti Bonnie Nijhof Ana Clara Fernandes Korinna Kochinke Anna Castells-Nobau Eva van Engelen Thijs Ellenkamp Lilian Eshuis Anne Galy Hans van Bokhoven Bianca Habermann Han G Brunner Christiane Zweier Patrik Verstreken Martijn A Huynen Annette Schenck |
| author_facet | Merel A W Oortveld Shivakumar Keerthikumar Martin Oti Bonnie Nijhof Ana Clara Fernandes Korinna Kochinke Anna Castells-Nobau Eva van Engelen Thijs Ellenkamp Lilian Eshuis Anne Galy Hans van Bokhoven Bianca Habermann Han G Brunner Christiane Zweier Patrik Verstreken Martijn A Huynen Annette Schenck |
| author_sort | Merel A W Oortveld |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T10:25:28Z |
| format | Article |
| id | doaj.art-ff42952b92fc4a049448b26baa6ad4b0 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-12T10:25:28Z |
| publishDate | 2013-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-ff42952b92fc4a049448b26baa6ad4b02022-12-22T03:36:59ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042013-10-01910e100391110.1371/journal.pgen.1003911Human intellectual disability genes form conserved functional modules in Drosophila.Merel A W OortveldShivakumar KeerthikumarMartin OtiBonnie NijhofAna Clara FernandesKorinna KochinkeAnna Castells-NobauEva van EngelenThijs EllenkampLilian EshuisAnne GalyHans van BokhovenBianca HabermannHan G BrunnerChristiane ZweierPatrik VerstrekenMartijn A HuynenAnnette SchenckIntellectual 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.http://europepmc.org/articles/PMC3814316?pdf=render |
| spellingShingle | Merel A W Oortveld Shivakumar Keerthikumar Martin Oti Bonnie Nijhof Ana Clara Fernandes Korinna Kochinke Anna Castells-Nobau Eva van Engelen Thijs Ellenkamp Lilian Eshuis Anne Galy Hans van Bokhoven Bianca Habermann Han G Brunner Christiane Zweier Patrik Verstreken Martijn A Huynen Annette Schenck Human intellectual disability genes form conserved functional modules in Drosophila. PLoS Genetics |
| title | Human intellectual disability genes form conserved functional modules in Drosophila. |
| title_full | Human intellectual disability genes form conserved functional modules in Drosophila. |
| title_fullStr | Human intellectual disability genes form conserved functional modules in Drosophila. |
| title_full_unstemmed | Human intellectual disability genes form conserved functional modules in Drosophila. |
| title_short | Human intellectual disability genes form conserved functional modules in Drosophila. |
| title_sort | human intellectual disability genes form conserved functional modules in drosophila |
| url | http://europepmc.org/articles/PMC3814316?pdf=render |
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