Dominant -catenin mutations cause intellectual disability with recognizable syndromic features. T. Kleefstra1, V. Tucci2,3, M. H. Willemsen1, A. Hardy3, I. Heise3, S. Maggi2, W. Wissink-Lindhout1, A. Vulto-van Silfhout1, B. B. A. deVries1, Z. Iqbal1, H. G. Brunner1, W. N. Nillesen1, H. G. Yntema1, H. Hilton3, M. Simon3, S. Tsaftaris4,5, H. van Bokhoven1, A. Constestabile2, T. Nieus2, A. Raimondi2, B. Greco2, D. Cantatore2, L. Gasparini2, L. Berdondini2, A. Bifone5, J. Veltman1, L. Peart-Vissers1, A. Gozzi5, S. Wells3, P. M. Nolan3 1) Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands; 2) Department of Neuroscience and Brain Technologies - Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genova; 3) MRC Harwell, Harwell Science and Innovation Campus, Oxfordshire, OX11 0RD, UK; 4) Instituto Italiano di Tecnologia, Center for Nanotechnology Innovation @NEST, Piazza San Silvestro 12, Pisa, Italy; 5) IMT Institute for Advanced Studies Lucca, Piazza San Ponziano 6, Lucca, Italy.
The recent identification of multiple dominant mutations in both humans and mice has enabled us to explore the molecular and cellular basis of -catenin function in cognitive impairment. Mutations in human CTNNB1 have been identified as causative in a spectrum of neurodevelopmental disorders. In identifying de novo CTNNB1 mutations in patients with intellectual disability and careful characterization of their phenotype, we were able to define a recognisable intellectual disability syndrome. In parallel, the characterization of a chemically-mutagenized mouseline displaying features that are similar to these human mutations hads enabled us to investigate the consequences of -catenin dysfunction through development and into adulthood. The mouse mutant displays a reduced affinity for membrane-associated cadherins in association with this decreased cadherin interaction. We find that the mutation results in decreased intrahemispheric connections with deficits in dendritic branching long-term potentiation and cognitive function. For the first time in vivo we show how dominant mutations in CTNNB1 underlie losses in its adhesion-related functions leading to severe consequences including intellectual disability, progressive spasticity and abnormal craniofacial features in humans.