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

## TL;DR

A genetic disorder called Baraitser-Winter Syndrome disrupts T-cell function, leading to immune problems, and treatments like IL-2 and dupilumab may help restore immune function.

## Contribution

This study is the first to link β-actin deficiency in BRWS1 to T-cell dysfunction and demonstrate potential therapeutic interventions.

## Key findings

- A novel ACTB mutation in BRWS1 causes defective T-cell synapse formation and reduced IL-2 production.
- Exogenous IL-2 and dupilumab treatment improved T-cell function and immune regulation in BRWS1.
- BRWS1 is identified as a primary immune regulatory disorder driven by actinopathy.

## Abstract

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.

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.

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.

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.

The online version contains supplementary material available at 10.1007/s10875-025-01906-x.