filamins

Filamins are large cytoskeletal proteins that cross-link actin filaments into three-dimensional networks and anchor them to membrane-associated proteins. The family comprises three paralogs in humans: filamin A (FLNA), filamin B (FLNB), and filamin C (FLNC). Each polypeptide contains an N-terminal actin-binding domain followed by a long rod of about 24 immunoglobulin-like repeats. The proteins form homodimers by antiparallel assembly of the rod regions, creating a flexible V-shaped scaffold capable of binding numerous partners.

Filamins organize the cortical actin network and serve as scaffolds that connect the cytoskeleton to transmembrane receptors such as integrins, growth factor receptors, and ion channels. They modulate signaling through interactions with Rho family GTPases, kinases, and adaptor proteins, contributing to cell shape, polarity, migration, adhesion, endocytosis, and mechanotransduction. Through these interactions, they influence processes from cell migration to tissue morphogenesis and response to mechanical cues.

FLNA is broadly expressed in many tissues, FLNB is enriched in mesenchymal and skeletal tissues, and FLNC is predominantly found in muscle and heart. Pathogenic variants in these genes underlie distinct clinical spectra. FLNA mutations cause X-linked disorders, most notably periventricular nodular heterotopia, with additional congenital heart defects and skeletal anomalies in some families. FLNB mutations produce skeletal dysplasias ranging from milder spondylocarpotarsal syndromes to severe boomerang dysplasia. FLNC variants are linked to muscular dystrophy and cardiomyopathy, including dilated forms and distal myopathy, with significant phenotypic variability.

In model systems, filamins are essential for normal development and tissue integrity; disruption can affect neuronal migration, cardiac and vascular formation, and skeletal patterning.