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GATAD2B loss-of-function mutations cause a recognisable syndrome with intellectual disability and are associated with learning deficits and synaptic undergrowth in Drosophila.
- Source :
-
Journal of medical genetics [J Med Genet] 2013 Aug; Vol. 50 (8), pp. 507-14. Date of Electronic Publication: 2013 May 04. - Publication Year :
- 2013
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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-of-function mutations in GATAD2B by whole exome sequencing in two unrelated individuals with severe intellectual disability.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Base Sequence
Child
Chromosome Deletion
DNA Copy Number Variations
Drosophila metabolism
Drosophila ultrastructure
Female
Humans
Molecular Sequence Data
Neurons metabolism
Repressor Proteins
Synapses genetics
Syndrome
Drosophila genetics
GATA Transcription Factors genetics
Intellectual Disability genetics
Learning Disabilities genetics
Mutation
Synapses metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 50
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 23644463
- Full Text :
- https://doi.org/10.1136/jmedgenet-2012-101490