| First Author | Tucci V | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 4 | Pages | 1468-82 |
| PubMed ID | 24614104 | Mgi Jnum | J:209611 |
| Mgi Id | MGI:5568180 | Doi | 10.1172/JCI70372 |
| Citation | Tucci V, et al. (2014) Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features. J Clin Invest 124(4):1468-82 |
| abstractText | 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. |
