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

• Published in: The Journal of clinical investigation Vol. 124; no. 4; pp. 1468 - 1482
• Main Authors: Tucci, Valter, Kleefstra, Tjitske, Hardy, Andrea, Heise, Ines, Maggi, Silvia, Willemsen, Marjolein H, Hilton, Helen, Esapa, Chris, Simon, Michelle, Buenavista, Maria-Teresa, McGuffin, Liam J, Vizor, Lucie, Dodero, Luca, Tsaftaris, Sotirios, Romero, Rosario, Nillesen, Willy N, Vissers, Lisenka E L M, Kempers, Marlies J, Vulto-van Silfhout, Anneke T, Iqbal, Zafar, Orlando, Marta, Maccione, Alessandro, Lassi, Glenda, Farisello, Pasqualina, Contestabile, Andrea, Tinarelli, Federico, Nieus, Thierry, Raimondi, Andrea, Greco, Barbara, Cantatore, Daniela, Gasparini, Laura, Berdondini, Luca, Bifone, Angelo, Gozzi, Alessandro, Wells, Sara, Nolan, Patrick M
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-04-2014
• Subjects: Adolescent; Adult; Amino Acid Sequence; Amino Acid Substitution; Animals; Base Sequence; beta Catenin - chemistry; beta Catenin - genetics; beta Catenin - metabolism; Brain - pathology; Cadherins; Cadherins - chemistry; Causes of; Child, Preschool; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - pathology; Disease Models, Animal; DNA - genetics; Female; Gene mutations; Genes, Dominant; Genetic aspects; Humans; Intellectual Disability - genetics; Male; Mental retardation; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Models, Molecular; Molecular Sequence Data; Multiprotein Complexes - chemistry; Multiprotein Complexes - genetics; Mutation; Phenotype; Sequence Homology, Amino Acid; Syndrome; Young Adult
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI70372

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.