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

American journal of human genetics

Authors: Nataliya Di Donato, Andrew Thom, Andreas Rump, Johannes N Greve, Juan Cadiñanos, Salvatore Calabro, Sara Cathey, Brian Chung, Heidi Cope, Maria 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 Pilz, Ivana Ricca, Fernando Santos Simarro, Evelin Schrock, Anja Marquardt, Manuel H Taft, Kamer Tezcan, Sofia Thunström, Judith 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

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.

Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

PMID: 41529692

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