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Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

Tucci, V., Kleefstra, T., Hardy, A., Heise, I., Maggi, S., Willemsen, M. H., Hilton, H., Esapa, C., Simon, M., Buenavista, M.-T., McGuffin, L. ORCID: https://orcid.org/0000-0003-4501-4767, Vizor, L., Dodero, L., Tsaftaris, S., Romero, R., Nillesen, W. N., Vissers, L. E. L. M., Kempers, M. J., Vulto-van Silfhout, A. T., Iqbal, Z. , Orlando, M., Maccione, A., Lassi, G., Farisello, P., Constestabile, A., Tinarelli, F., Nieus, T., Raimondi, A., Greco, B., Cantatore, D., Gasparini, L., Berdondini, L., Bifone, A., Gozzi, A., Wells, S. and Nolan, P. M. (2014) Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features. The Journal of Clinical Investigation, 124 (4). pp. 1468-1482. ISSN 0021-9738

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To link to this item DOI: 10.1172/JCI70372

Abstract/Summary

The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-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 β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of β-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 β-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

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:36195
Publisher:American Society for Clinical Investigation

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