Human intellectual disability genes form conserved functional modules in Drosophila
- PMID: 24204314
- PMCID: PMC3814316
- DOI: 10.1371/journal.pgen.1003911
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.
Conflict of interest statement
The authors have declared that no competing interests exist.
Figures
Similar articles
-
Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.Biol Psychiatry. 2019 Aug 15;86(4):294-305. doi: 10.1016/j.biopsych.2019.04.029. Epub 2019 May 9. Biol Psychiatry. 2019. PMID: 31272685 Free PMC article.
-
Systematic Phenomics Analysis Deconvolutes Genes Mutated in Intellectual Disability into Biologically Coherent Modules.Am J Hum Genet. 2016 Jan 7;98(1):149-64. doi: 10.1016/j.ajhg.2015.11.024. Am J Hum Genet. 2016. PMID: 26748517 Free PMC article.
-
Drosophila models of early onset cognitive disorders and their clinical applications.Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:326-42. doi: 10.1016/j.neubiorev.2014.01.013. Epub 2014 Mar 21. Neurosci Biobehav Rev. 2014. PMID: 24661984 Review.
-
GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila.J Med Genet. 2013 Aug;50(8):507-14. doi: 10.1136/jmedgenet-2012-101490. Epub 2013 May 4. J Med Genet. 2013. PMID: 23644463
-
Molecular basis for prospective pharmacological treatment strategies in intellectual disability syndromes.Dev Neurobiol. 2014 Feb;74(2):197-206. doi: 10.1002/dneu.22093. Epub 2013 Jul 19. Dev Neurobiol. 2014. PMID: 23695997 Review.
Cited by
-
Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.Hum Mol Genet. 2015 Dec 1;24(23):6736-55. doi: 10.1093/hmg/ddv380. Epub 2015 Sep 16. Hum Mol Genet. 2015. PMID: 26376863 Free PMC article.
-
Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis.BMC Biol. 2024 Jan 2;22(1):2. doi: 10.1186/s12915-023-01800-1. BMC Biol. 2024. PMID: 38167120 Free PMC article.
-
Dissecting the complexity of CNV pathogenicity: insights from Drosophila and zebrafish models.Curr Opin Genet Dev. 2021 Jun;68:79-87. doi: 10.1016/j.gde.2021.02.013. Epub 2021 Mar 31. Curr Opin Genet Dev. 2021. PMID: 33812298 Free PMC article. Review.
-
Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.Biol Psychiatry. 2019 Aug 15;86(4):294-305. doi: 10.1016/j.biopsych.2019.04.029. Epub 2019 May 9. Biol Psychiatry. 2019. PMID: 31272685 Free PMC article.
-
Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms.J Neurodev Disord. 2015;7(1):18. doi: 10.1186/s11689-015-9113-x. Epub 2015 Jul 1. J Neurodev Disord. 2015. PMID: 26137170 Free PMC article.
References
-
- Ropers HH (2010) Genetics of early onset cognitive impairment. Annu Rev Genomics Hum Genet 11: 161–187. - PubMed
-
- van Bokhoven H (2011) Genetic and Epigenetic Networks in Intellectual Disabilities. Annual Review of Genetics 45: 81–104. - PubMed
-
- Krab LC, Goorden SM, Elgersma Y (2008) Oncogenes on my mind: ERK and MTOR signaling in cognitive diseases. Trends Genet 24: 498–510. - PubMed
-
- Najmabadi H, Hu H, Garshasbi M, Zemojtel T, Abedini SS, et al. (2011) Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478: 57–63. - PubMed
Publication types
MeSH terms
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases