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Purpose <p>Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in <i>ACTB</i>, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of <i>ACTB</i> mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel <i>ACTB</i> variant in a patient with BRWS1.</p> Methods <p>Whole-exome sequencing identified a heterozygous <i>ACTB</i> p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant <i>ACTB</i> constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated.</p> Results <p>The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation.</p> Conclusion <p>BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.</p>

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β-Actin Deficiency in Baraitser-Winter Syndrome Type 1 Disrupts T-Cell Function and Immune Regulation: Implications for Targeted Therapy in Actinopathies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月1日

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  • Zahala Bar-On,
  • Or Reuven,
  • Atar Lev,
  • Amos J. Simon,
  • Wajeeh Salaymeh,
  • Alit Shalom,
  • Raz Somech,
  • Ortal Barel,
  • Sigal Porges,
  • Elisheva Javasky,
  • Vered Molho-Pessach,
  • Zvi Granot,
  • Dan Bijaoui,
  • Tzahi Neuman,
  • Yuval Tal,
  • Michal Baniyash,
  • Michael Berger,
  • Oded Shamriz

摘要

Purpose

Baraitser-Winter syndrome type 1 (BRWS1) is a rare disorder characterized by intellectual disability, short stature, facial dysmorphism, cortical malformations, macrothrombocytopenia, and recurrent infections. BRWS1 is caused by loss-of-function variants in ACTB, leading to β-actin deficiency. Given the essential role of the actin cytoskeleton in T-cell activation, the immunological consequences of ACTB mutations remain unexplored. Here, we characterize immune dysfunction associated with a novel ACTB variant in a patient with BRWS1.

Methods

Whole-exome sequencing identified a heterozygous ACTB p.Gln360ProfsTer4 variant in a patient with BRWS1 and combined immunodeficiency. Functional studies were performed in HEK293T cells transfected with wild-type and mutant ACTB constructs. Patient-derived T cells were analyzed for immunological synapse formation, cytokine production, activation, and proliferation. The therapeutic effects of exogenous IL-2 and dupilumab were evaluated.

Results

The mutant β-actin protein was rapidly degraded and exerted a dominant-negative effect on wild-type β-actin, thereby disrupting cytoskeletal integrity. Patient-derived T cells demonstrated defective immunological synapse formation, reduced intra-synaptic IL-2 levels, and impaired activation and proliferation. Supplementation with exogenous IL-2 partially restored T-cell function in vitro. Notably, dupilumab treatment led to significant clinical and immunological improvement, suggesting a role in restoring immune regulation.

Conclusion

BRWS1 represents a novel primary immune regulatory disorder. Our findings highlight actinopathy-driven immunodeficiency as a target for therapeutic intervention, with broader implications for cytoskeletal disorders.