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.
Since only 20% of female fragile X premutation carriers develop premature ovarian failure (POF, i.e., amenorrhea before age of 40 years), and since X chromosome inactivation (XCI) determines the phenotypic severity of full mutation women, we reasoned that the development of POF in fragile X premutation carriers could be due to skewed XCI (XCI ratio >80:20). To determine inactivation ratios and activities of the premutations, inactivation patterns were assessed in peripheral blood samples from 101 fragile X premutation carriers (mean age 47.1 years, range 12-72) through analysis of the AR and FMR1 loci, respectively. In addition, AR inactivation patterns were assessed in peripheral blood samples from 25 women with idiopathic POF (mean age 31.7 years, range 19-48). We addressed the association between age and skewed XCI because older women are prone to XCI skewness. The median XCI ratios were 68% for premutation carriers with POF (N = 37), 67% for premutation carriers without POF (N = 64) and 61% for women with idiopathic POF (N = 25). The incidence of skewing was similar in all groups, that is, 7 of 37 (18.9%) in premutation carriers with POF, 11 of 64 (17.2%) in premutation carriers without POF, and 3 of 25 (12%) in women with idiopathic POF. There was good concordance between inactivation ratios at the two loci tested in 62 premutation carriers (intraclass correlation coefficient = 0.86; P < 0.01). No age-specific skewing was observed. Skewed XCI and activity of the premutation are not associated with POF in fragile X premutation carriers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.