Author(s):
|
Tucci, V.;
Kleefstra, T.
; Hardy, A.; Heise, I.; Maggi, S.;
Willemsen, M.H.
; Hilton, H.; Esapa, C.; Simon, M.; Buenavista, M.T.; McGuffin, L.J.; Vizor, L.; Dodero, L.; Tsaftaris, S.; Romero, R.; Nillesen, W.N.;
Vissers, L.E.L.M.
;
Kempers, M.J.E.
;
Silfhout, A.T. van
;
Iqbal, Z.
; Orlando, M.; Maccione, A.; Lassi, G.; Farisello, P.; Contestabile, A.; Tinarelli, F.; Nieus, T.; Raimondi, A.; Greco, B.; Cantatore, D.; Gasparini, L.; Berdondini, L.; Bifone, A.; Gozzi, A.; Wells, S.; Nolan, P.M.
|
Subject:
|
Radboudumc 0: Other Research DCMN: Donders Center for Medical Neuroscience Radboudumc 16: Vascular damage RIHS: Radboud Institute for Health Sciences Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience Radboudumc 7: Neurodevelopmental disorders RIMLS: Radboud Institute for Molecular Life Sciences |
Organization:
|
Human Genetics Primary and Community Care |
Journal title:
|
Journal of Clinical Investigation
|
Abstract:
|
The recent identification of multiple dominant mutations in the gene encoding beta-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of beta-catenin function in cognitive impairment. In humans, beta-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo beta-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 beta-catenin mutations enabled us to investigate the consequences of beta-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (Bfc), carries a Thr653Lys substitution in the C-terminal armadillo repeat of beta-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 beta-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.
|