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Background <p><i>CTNNB1</i> syndrome is a rare disorder caused by pathogenic variants of <i>CTNNB1</i> gene, resulting in intellectual disability, peripheral spasticity, cognitive and motor impairments. The <i>CTNNB1</i> encodes the <i>β</i>-catenin protein, which plays dual roles in cells by forming synaptic adhesion through the <i>E</i>-cadherin<i>/</i>catenin adhesion complex and the activation of the Wnt signaling pathway.</p> Methods and results <p>In this study, we describe for the first time a <i>CTNNB1</i> syndrome in Tunisian children, by the description of two unrelated Tunisian patients with spastic paraplegia, intellectual disability and visual defect using whole exome sequencing. We identified a de novo nonsense (c.999&#xa0;C &gt; A; p.Tyr333X) mutation and a novel de novo frameshift variant (c.1041–1044 del; p.Val349Alafs*9) in the <i>CTNNB1</i> gene, which were predicted to be pathogenic using in silico investigations. The identified (c.1041–1044 del) would lead to a frameshift followed by a premature stop codon, generating a nonsense mRNA that would probably escape nonsense-mediated decay. Thus, the nonsense mRNA could result in the premature translation termination and synthesis of dysfunctional protein with largely truncated ARM domains. The consequences of <i>CTNNB1</i> frameshift variant were further explored together with wildtype through molecular docking and molecular dynamics simulations, which uncovered the disruption of <i>β</i>-catenin function and the loss of its interacting counterparts. Hence, molecular dynamics simulation provides a comprehensive understanding of the conformational changes, compactness, folding and stability of the mutated <i>β</i>-catenin protein.</p> Conclusions <p>We present the first description of <i>CTNNB1</i> syndrome in the Tunisian population and provide new insights into the usefulness of computational approaches to enlighten the molecular consequences of the frameshift variant p.Val349Alafs*9.</p>

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The first description of CTNNB1 syndrome in the Tunisian population: clinical investigation, molecular docking and molecular dynamics simulation of β-catenin/E-cadherin complex

  • 期刊论文

  • 发表日期：

    2025年10月25日

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  • Marwa Kharrat,
  • Wafa bouchaala,
  • Magdy M. D. Mohammed,
  • Abir ben issa,
  • Faiza Fakhfakh,
  • Fatma kamoun,
  • Chahnez Triki

摘要

Background

CTNNB1 syndrome is a rare disorder caused by pathogenic variants of CTNNB1 gene, resulting in intellectual disability, peripheral spasticity, cognitive and motor impairments. The CTNNB1 encodes the β-catenin protein, which plays dual roles in cells by forming synaptic adhesion through the E-cadherin/catenin adhesion complex and the activation of the Wnt signaling pathway.

Methods and results

In this study, we describe for the first time a CTNNB1 syndrome in Tunisian children, by the description of two unrelated Tunisian patients with spastic paraplegia, intellectual disability and visual defect using whole exome sequencing. We identified a de novo nonsense (c.999 C > A; p.Tyr333X) mutation and a novel de novo frameshift variant (c.1041–1044 del; p.Val349Alafs*9) in the CTNNB1 gene, which were predicted to be pathogenic using in silico investigations. The identified (c.1041–1044 del) would lead to a frameshift followed by a premature stop codon, generating a nonsense mRNA that would probably escape nonsense-mediated decay. Thus, the nonsense mRNA could result in the premature translation termination and synthesis of dysfunctional protein with largely truncated ARM domains. The consequences of CTNNB1 frameshift variant were further explored together with wildtype through molecular docking and molecular dynamics simulations, which uncovered the disruption of β-catenin function and the loss of its interacting counterparts. Hence, molecular dynamics simulation provides a comprehensive understanding of the conformational changes, compactness, folding and stability of the mutated β-catenin protein.

Conclusions

We present the first description of CTNNB1 syndrome in the Tunisian population and provide new insights into the usefulness of computational approaches to enlighten the molecular consequences of the frameshift variant p.Val349Alafs*9.