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. Introduction β-Catenin (CTNNB1) is a highly conserved protein that implements key cellular functions by interacting with cell-adhesion proteins, signaling molecules, and transcription factors (1). The characteristic structural feature of the β-catenin protein, its 12 central armadillo repeats, forms a long positively charged groove facilitating interaction with multiple protein partners. This central motif is flanked by the N terminus, crucial in mediating degradation of the protein, and the C terminus, containing the Helix-C motif (2), which enables switching between the protein's dual roles in cell adhesion and proliferation. Loss-of-function studies in mammals have implicated β-catenin in embryonic development, while gain-of-function studies have demonstrated its contribution to various forms of human cancers (reviewed in ref.3). Functional investigation has focused on the role of β-catenin in canonical WNT signaling. β-Catenin interacts with transcriptional coactivators to mediate WNT's transcriptional activation, which orchestrates growth and patterning in the developing embryo, and, when constitutively upregulated, dysregulates growth connected to cancer and metastasis.

WNT/β-Catenin Pathway and Epigenetic Mechanisms Regulate the Pitt-Hopkins Syndrome and Schizophrenia Risk Gene TCF4

“…Indeed, recurrent disruptive mutations in CTNNB1 were found in targeted large-scale resequencing studies in the study of autism spectrum disorders [64]. Moreover, a new intellectual disability and neurodevelopment syndrome was recently reported with the discovery of a total of 20 individuals (from 19 different families) with de novo, heterozygous, loss-of-function mutations in CTNNB1 [65,66,67]. In addition to intellectual disability, affected individuals with CTNNB1 haploinsufficiency were described to commonly show motor delay, severe speech impairment, microcephaly, and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity) with characteristic facial features consisting of abnormal nasal and lip structures [65,66,67].…”

“…Moreover, a new intellectual disability and neurodevelopment syndrome was recently reported with the discovery of a total of 20 individuals (from 19 different families) with de novo, heterozygous, loss-of-function mutations in CTNNB1 [65,66,67]. In addition to intellectual disability, affected individuals with CTNNB1 haploinsufficiency were described to commonly show motor delay, severe speech impairment, microcephaly, and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity) with characteristic facial features consisting of abnormal nasal and lip structures [65,66,67]. Since a number of these features are reminiscent of the clinical diagnosis of PTHS, given our findings suggesting the direct regulation of TCF4 in a WNT/β-catenin-dependent manner, this suggests that both haploinsufficiency disorders may share a common molecular pathogenesis, with the prediction from our work that individuals with reduced β-catenin function will have decreased TCF4 expression.…”

Cadherins and catenins in dendrite and synapse morphogenesis

“…Indeed in many genome-wide association studies cadherins have been associated with autism, bipolar disease or schizophrenia as well as with Alzheimer's disease. It is noteworthy that not only cadherin superfamily members but also the catenins, aNcatenin, b-catenin and d-catenin, have been repeatedly associated with these neural disorders [77][78][79] (Table 2).…”

N-cadherin-based adherens junction regulates the maintenance, proliferation, and differentiation of neural progenitor cells during development

“…107,108 The portion of this repetitive sequence combines with the cytoplasmic region of N-cadherin, or APC, and Axin. 109 This N-cadherin binding site and the APC and Axin binding sites overlap, so b-catenin cannot combine with N-cadherin and the APC or Axin simultaneously (Fig. 5).…”