[Overview of cytoskeletal actin mutations associated with rare diseases]

Dynamics of the actin cytoskeleton play an important role in many physiological processes. Mutations in actin and actin-binding proteins cover a wide spectrum of diseases, called actinopathies. Of the six actin isoforms, the cytoskeletal β- and γ-actin isoforms differ from each other by only four amino acids. This results in overlapping and isoform-specific functions. Mutations in the ACTB and ACTG1 genes have been associated with rare diseases, so-called non-muscle actinopathies (NMA). The phenotype of affected individuals covers a wide clinical spectrum - from asymptomatic variants to mutations with severe intellectual disability and organ damage - which is related to the specific ACTB or ACTG1 variant. Recent studies have attempted to group mutations associated with different NMAs based on the genotype-clinical phenotype-molecular mechanism relationship by comparing clinical phenotype from patient databases and biochemical data. Based on all this, Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) patients constitute one of the (most severe) groups, to which patients diagnosed with characteristic facial dysmorphism and frontal pachygyria can be classified. Based on the molecular mechanism of these mutations, the dynamics of the actin filaments are affected. Patients in the group diagnosed with ACTB pLoF (predicted loss-of-function) disorder show facial dysmorphism that is different from the BWCFF group, but characteristic of the group, with mild developmental abnormalities and immunological symptoms. These mutations lead to reduced expression or reduced stability of the protein at the molecular level. The other patient groups show different phenotypes at the clinical level, for which, to our current knowledge, no specific molecular mechanism has been identified. In this review, we aim to provide a comprehensive picture of the genotype-clinical phenotype-molecular mechanism relationship, detailing the molecular background of the clinical variants described so far, touching on actin isoform-specific differences, and outlining future research directions. Orv Hetil. 2026; 167(19): 731-739.