Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features
SourceJournal of Clinical Investigation, 124, 4, (2014), pp. 1468-1482
Article / Letter to editor
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Primary and Community Care
Journal of Clinical Investigation
SubjectRadboudumc 0: Other Research DCMN: Donders Center for Medical Neuroscience; Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Radboudumc 7: Neurodevelopmental disorders RIMLS: Radboud Institute for Molecular Life Sciences
The recent identification of multiple dominant mutations in the gene encoding beta-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of beta-catenin function in cognitive impairment. In humans, beta-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo beta-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with beta-catenin mutations enabled us to investigate the consequences of beta-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of beta-catenin and displayed a reduced affinity for membrane-associated cadherins. In association with this decreased cadherin interaction, we found that the mutation results in decreased intrahemispheric connections, with deficits in dendritic branching, long-term potentiation, and cognitive function. Our study provides in vivo evidence that dominant mutations in beta-catenin underlie losses in its adhesion-related functions, which leads to severe consequences, including intellectual disability, childhood hypotonia, progressive spasticity of lower limbs, and abnormal craniofacial features in adults.
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