The Baraitser–Winter Cerebrofrontofacial Syndrome Recurrent R196H Variant in Cytoplasmic β‐Actin Impairs Its Cellular Polymerization and Stability

作者：Éva Gráczer, Elena Battirossi, Tamás Bozó, Á. Altorjay, Katalin Pászty, Laura Harsányi, Johannes N. Greve, Irene Pertici, M. Reconditi, Nataliya Di Donato, Miklós Kellermayer, Pasquale Bianco, Andréa Varga · 发表于：The FASEB Journal · 年份：2026 · DOI：10.1096/fj.202502196r · 被引用次数：2 · 研究领域：Craniofacial Disorders and Treatments、Skin and Cellular Biology Research、Microtubule and mitosis dynamics

Variants in cytoskeletal actin encoding genes are associated with a broad spectrum of disorders, called non-muscle actinopathies. Among them, the Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) displays the most severe symptoms, such as intellectual disability and epilepsy. We found that the BWCFF-associated R196H mutation results in reduced proliferation and migration of patient-derived fibroblast cells, and the latter is likely related to decreased fibronectin expression. The mutation causes a 50% drop in filamentous (F-) actin content, which is correlated with an approximately fourfold reduction in the stiffness of patient-derived cells probed with atomic force microscopy (AFM). We observed no significant defects either in the organization of the cellular actin cytoskeleton, analyzed by superresolution (STED) microscopy, or in the structure of purified filaments, explored with AFM. On the other hand, the more parallel orientation of the mutant actin bundles might be caused by the perturbed interaction of actin with the Arp2/3 complex. Manipulating the cells by mechanical forces through the application of the dual laser optical tweezers (DLOT) technique suggests that the mutation weakens the attachment of cytoskeletal actin to the plasma membrane. Inducing dynamic reorganization of actin by uniaxial stretching revealed that the interaction of cofilin with actin is also weakened by the mutation. Thus, the impaired function of actin to form filaments and interact with e...