Authors
Di Donato N; NMA Consortium; Thom A, Rump A, Greve JN, Cadiñanos J, Calabro S, Cathey S, Chung B, Cope H, Costales M, Cuvertino S, Dinkel P, Erripi K, Fry AE, Garavelli L, Hoffjan S, Janzarik WG, Kreimer I, Mancini G, Marin-Reina P, Meinhardt A, Niehaus I, Pilz D, Ricca I, Simarro FS, Schrock E, Marquardt A, Taft MH, Tezcan K, Thunström S, Verhagen J, Verloes A, Wollnik B, Krawitz P, Hsieh TC, Seifert M, Heide M, Lawrence CB, Roberts NA, Manstein DJ, Woolf AS, Banka S
Journal
American Journal of Human Genetics
Citation
Am J Hum Genet. 2026 Jan 12:S0002-9297(25)00478-1.
Abstract
Recent advances in Mendelian genomics reveal the importance of variant-level characterization of allelic disorders. Non-muscle actin isoforms, encoded by the genes ACTB and ACTG1, are the most abundant intracellular proteins, but historically, they are often regarded as merely being „housekeeping“ molecules. Here, we illuminate the extraordinary clinical heterogeneity and complex pathobiology of genetic non-muscle actinopathies. To do this, we combine human genomics studies with molecular biology. Strikingly, variants in ACTB and ACTG1 isoforms generate at least eight distinct clinical disorders. A subset of disease-associated missense variants causes dysregulated actin polymerization-depolymerization and neuronal migration defects. In contrast, nonsense, frameshift, and missense variants enhancing protein degradation cause milder phenotypes or are benign. These results emphasize the essential functional aspects of the non-muscle actin isoforms. Critically, they additionally constitute a template for the personalized genetic variant-level-driven management of the pleiotropic allelic single-gene disorders.
