title: 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.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Andrea
authors.initials: A
authors.lastname: Hardy
authors.forename: Ines
authors.initials: I
authors.lastname: Heise
authors.forename: Silvia
authors.initials: S
authors.lastname: Maggi
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.forename: Helen
authors.initials: H
authors.lastname: Hilton
authors.forename: Chris
authors.initials: C
authors.lastname: Esapa
authors.forename: Michelle
authors.initials: M
authors.lastname: Simon
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Buenavista
authors.forename: Liam J
authors.initials: LJ
authors.lastname: McGuffin
authors.forename: Lucie
authors.initials: L
authors.lastname: Vizor
authors.forename: Luca
authors.initials: L
authors.lastname: Dodero
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsaftaris
authors.forename: Rosario
authors.initials: R
authors.lastname: Romero
authors.forename: Willy N
authors.initials: WN
authors.lastname: Nillesen
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Marlies J
authors.initials: MJ
authors.lastname: Kempers
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.forename: Marta
authors.initials: M
authors.lastname: Orlando
authors.forename: Alessandro
authors.initials: A
authors.lastname: Maccione
authors.forename: Glenda
authors.initials: G
authors.lastname: Lassi
authors.forename: Pasqualina
authors.initials: P
authors.lastname: Farisello
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.forename: Federico
authors.initials: F
authors.lastname: Tinarelli
authors.forename: Thierry
authors.initials: T
authors.lastname: Nieus
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.forename: Barbara
authors.initials: B
authors.lastname: Greco
authors.forename: Daniela
authors.initials: D
authors.lastname: Cantatore
authors.forename: Laura
authors.initials: L
authors.lastname: Gasparini
authors.forename: Luca
authors.initials: L
authors.lastname: Berdondini
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzi
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Nolan
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000473:pathology; D015820:Cadherins / Q000737:chemistry; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D055815:Young Adult; D051176:beta Catenin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D046912:Multiprotein Complexes; D051176:beta Catenin; D004247:DNA