GATAD2Bloss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth inDrosophila

Abstract

Background GATA zinc finger domain containing 2B (GATAD2B) encodes a subunit of the MeCP1-Mi-2/ nucleosome remodelling and deacetylase complex involved in chromatin modification and regulation of transcription. We recently identified two de novo loss-offunction mutations in GATAD2B by whole exome sequencing in two unrelated individuals with severe intellectual disability. Methods To identify additional individuals with GATAD2B aberrations, we searched for microdeletions overlapping with GATAD2B in inhouse and international databases, and performed targeted Sanger sequencing of the GATAD2B locus in a selected cohort of 80 individuals based on an overlap with the clinical features in the two index cases. To address whether GATAD2B is required directly in neurones for cognition and neuronal development, we investigated the role of Drosophila GATAD2B orthologue simjang (simj) in learning and synaptic connectivity. Results We identified a third individual with a 240 kb microdeletion encompassing GATAD2B and a fourth unrelated individual with GATAD2B loss-of-function mutation. Detailed clinical description showed that all four individuals with a GATAD2B aberration had a distinctive phenotype with childhood hypotonia, severe intellectual disability, limited speech, tubular shaped nose with broad nasal tip, short philtrum, sparse hair and strabismus. Neuronal knockdown of Drosophila GATAD2B orthologue, simj, resulted in impaired learning and altered synapse morphology. Conclusions We hereby define a novel clinically recognisable intellectual disability syndrome caused by loss-of-function of GATAD2B. Our results in Drosophila suggest that GATAD2B is required directly in neurones for normal cognitive performance and synapse development.

Dicholine succinate, the neuronal insulin sensitizer, normalizes behavior, REM sleep, hippocampal pGSK3 beta and mRNAs of NMDA receptor subunits in mouse models of depression

“…VGF and Egr1 were found to enhance hippocampal synaptic plasticity and neurogenesis (Thakker-Varia and Alder, 2009). GATAD2B was shown to be required for normal cognitive performance and synapse development (Willemsen et al, 2013). …”

De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila

“…RNAi was induced using the UAS-Gal4 system and the panneuronal driver lines: elav-Gal4 w 1118 ; 2xGMR-wIR; elav-Gal4, UAS-Dicer-2 or nSyb-Gal4 w 1118 , UAS-Dicer-2; nSyb-Gal4.. 9,24 Flies were reared and tested at 25°C (elav-Gal4) and 28°C (nSyb-Gal4) and 70% humidity. The ubiquitous actin-Gal4 driver w 1118 ; P(w[+mC] = Act5c-Gal4)/CyO obtained from Bloomington Drosophila Stock Center, 25 was used to generate RNAi-mediated knockdown for quantitative PCR (qPCR).…”

“…31,32 Using the light-off jump reflex habituation, we have previously identified learning deficits in number of Drosophila ID models. 9,24,26 Two independent inducible RNAi lines targeting the Drosophila WAC orthologue CG8949 (vdrc48307 and vdrc107328) and their corresponding genetic background control lines (vdrc60000 and vdrc60100) were obtained (Vienna Drosophila RNAi Center 22 ) and fly stocks were kept under standard conditions. Expression of CG8949 was specifically downregulated in neurons using the UAS-Gal4 system.…”

“…Furthermore, supporting evidence and insights into underlying mechanisms can be obtained from functional studies in cell or animal models. 8,9 Previously, we and others separately reported on an individual with a de novo mutation in the 'WW domain-containing adapter with coiled-coil' (WAC) gene using trio-based exome sequencing. 1, 10 The mutations were reported as potential cause of disease, based on mutation severity, protein function, its expression in fetal stages and high expression in adult brain.…”

Zinc-Finger Proteins in Brain Development and Mental Illness

“…Recently, several papers reported that de novo mutation of GATAD2b gene, a subunit of the methyl-CpG-binding protein-1 complex (MECP1), causes severe intellectual disability [30][31][32]. GATAD2b contains only one GATA type zinc finger domain ( Figure 1) is a transcription repressor through deacetylating methylated nucleosomes.…”