Making connections

Mutations within the gene encoding β-catenin (CTNNB1) are associated with an array of neurodevelopmental disorders, including autism spectrum disorders. Valter Tucci and colleagues identified dominant CTNNB1 mutations in patients with intellectual disability that all displayed a syndrome characterized by mild to severe intellectual disability, autism, lack of muscle tone, progressive limb spasticity, and craniofacial abnormalities. Characterization of a mutagenized mouse strain (Bfc) that displays similar features to patients and harbors a dominant Ctnnb1 mutation revealed that the mutated from of β-catenin has a reduced affinity for cadherins, resulting in decreased dendritic branching, a decline in long-term potentiation, and loss of cognitive function. The accompanying diffusion tensor image (DTI) trajectories in the corpus callosum of a control animal (right) and a Bfc mouse reveal (left) a lack of interhemispheric extensions as the result of Ctnnb1 mutation.

Published March 10, 2014, by Corinne Williams

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Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features
Valter Tucci, … , Sara Wells, Patrick M. Nolan
Valter Tucci, … , Sara Wells, Patrick M. Nolan
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1468-1482. https://doi.org/10.1172/JCI70372.
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Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features

Abstract

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.

Authors

Valter Tucci, Tjitske Kleefstra, Andrea Hardy, Ines Heise, Silvia Maggi, Marjolein H. Willemsen, Helen Hilton, Chris Esapa, Michelle Simon, Maria-Teresa Buenavista, Liam J. McGuffin, Lucie Vizor, Luca Dodero, Sotirios Tsaftaris, Rosario Romero, Willy N. Nillesen, Lisenka E.L.M. Vissers, Marlies J. Kempers, Anneke T. Vulto-van Silfhout, Zafar Iqbal, Marta Orlando, Alessandro Maccione, Glenda Lassi, Pasqualina Farisello, Andrea Contestabile, Federico Tinarelli, Thierry Nieus, Andrea Raimondi, Barbara Greco, Daniela Cantatore, Laura Gasparini, Luca Berdondini, Angelo Bifone, Alessandro Gozzi, Sara Wells, Patrick M. Nolan

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