Dominant ?-catenin mutations cause intellectual disability with recognizable syndromic features.

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

SUBMITTER: Tucci V 

PROVIDER: S-EPMC3973091 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature