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
; 50(8): 507-14, 2013 Aug.
Article
em En
| MEDLINE
| ID: mdl-23644463
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.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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Drosophila
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Fatores de Transcrição GATA
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Deficiências da Aprendizagem
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Deficiência Intelectual
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Mutação
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Child
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Female
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Humans
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Holanda