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

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 IqbalMarta 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

Research output: Contribution to journalArticle (Academic Journal)peer-review

82 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1468-82
Number of pages15
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - Apr 2014


  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Brain
  • Cadherins
  • Child, Preschool
  • Craniofacial Abnormalities
  • DNA
  • Disease Models, Animal
  • Female
  • Genes, Dominant
  • Humans
  • Intellectual Disability
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Mutation
  • Phenotype
  • Sequence Homology, Amino Acid
  • Syndrome
  • Young Adult
  • beta Catenin
  • Case Reports
  • Journal Article
  • Research Support, Non-U.S. Gov't


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