Dominant β-catenin mutations cause intellectual disability with recognizable syndromic features
Valter Tucci, … , Sara Wells, Patrick M. Nolan
Valter Tucci, … , Sara Wells, Patrick M. Nolan
Published March 10, 2014
Citation Information: J Clin Invest. 2014;124(4):1468-1482. https://doi.org/10.1172/JCI70372.
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Research Article Neuroscience

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

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 Iqbal, Marta 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

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Figure 7

Morphological and functional deficits in Bfc/+ primary hippocampal neuronal cultures.

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Morphological and functional deficits in Bfc/+ primary hippocampal neuro...
(A) Representative images of primary cultures of +/+ and Bfc/+ hippocampal neurons after 8 days in culture. Scale bars are as indicated. Primary processes are shown in green, secondary processes in yellow. (B) Number of processes and neurite length are presented. Processes are significantly less in Bfc/+ neurons. *P = 0.02, 2-tailed t test. (C) Representative images of neuronal cultures transfected at 1 DIV with β-catenin or control siRNA and fixed at 7 DIV. (D) siRNA against β-catenin efficiently decreased mRNA expression, as assessed by RT-qPCR (P < 0.01), while neurite extension was significantly reduced (*P < 0.05) in β-catenin–transfected neurons. (E) In vitro neuronal network set-up showing (left to right) the high-density MEA chip, fluorescence image of the low density culture (β3-tubulin green, NeuN red) showing the sparse network distribution on a portion of the electrode array (black square), raw data traces of spiking activity acquired from 3 different channels, raster plot of approximately 400 active channels (i.e., firing rate > 0.1 spike/s) showing synchronous firing and sustained bursting activity. (F–I) cumulative distributions of network parameters (+/+ black, n = 4; Bfc/+ red, n = 6). Bold lines and shaded regions correspond to mean ± SEM. The Bfc/+ cultures were more excitable, as evidenced by the higher MFR (F) and MBR (G). Less evident is the variation for the MBD (H). The functional connectivity analysis based on cross-correlation shows that functional link length was also higher in Bfc/+ (I).