Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies

作者：Nataliya Di Donato, Andrew Thom, Andreas Rump, Johannes N. Greve, Juan Enrique Cadiñanos, Salvatore Calabro, Sara E. Cathey, Brian Chung, Heidi L. Cope, María Costales, Sara Cuvertino, Philine Dinkel, Kalliopi Erripi, Andrew E. Fry, Livia Garavelli, Sabine Hoffjan, Wibke G. Janzarik, Insa Kreimer, Grazia Mancini, Purificacion Marin-Reina, Andrea Meinhardt, Indra Niehaus, Daniela T. Pilz, Ivana Ricca, Fernando Santos‐Simarro, Evelin Schröck, Anja Marquardt, Manuel H. Taft, Kamer Tezcan, Sofia Thunström, Judith M.A. Verhagen, Alain Verloes, Bernd Wollnik, Peter Krawitz, Tzung-Chien Hsieh, Michael Seifert, Michael Heide, Catherine B. Lawrence, Neil A. Roberts, Dietmar J. Manstein, Adrian S. Woolf, Siddharth Banka · 发表于：The American Journal of Human Genetics · 年份：2026 · DOI：10.1016/j.ajhg.2025.12.007 · 被引用次数：4 · 研究领域：Genomics and Rare Diseases、Genetics and Physical Performance、Cardiomyopathy and Myosin Studies

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.