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

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.

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Publication Details

Journal
The American Journal of Human Genetics
Published
2026-01-12
DOI
https://doi.org/10.1016/j.ajhg.2025.12.007
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
30.93

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article

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

Michael Heide, Nataliya Di Donato, Judith M.A. Verhagen, Peter Krawitz et al.
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The American Journal of Human Genetics
Genomics and Rare Diseases
30.93
article

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

Michael Heide, Nataliya Di Donato, Judith M.A. Verhagen, Peter Krawitz, Anja Marquardt, Alain Verloes, Johannes N. Greve, Sara Cuvertino, Manuel H. Taft, Juan Enrique Cadiñanos, Philine Dinkel, Fernando Santos‐Simarro, Sara E. Cathey, Andreas Rump, Heidi L. Cope, Evelin Schröck, Daniela T. Pilz, Purificacion Marin-Reina, Neil A. Roberts, Michael Seifert, Insa Kreimer, Indra Niehaus, Kalliopi Erripi, Grazia Mancini, Catherine B. Lawrence, Sofia Thunström, Andrew E. Fry, Adrian S. Woolf, Sabine Hoffjan, Brian Chung, Andrea Meinhardt, Kamer Tezcan, Salvatore Calabro, Wibke G. Janzarik, Siddharth Banka, Livia Garavelli, Maria Costales, Dietmar J. Manstein, Andrew Thom, Ivana Ricca, Bernd Wollnik
article en
1 citations

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.

The American Journal of Human GeneticsVol. 113(2)
Kaiser Permanente (US), University of Bonn (DE), University of Freiburg (DE), Délégation Paris 7 (FR), Université Paris Cité (FR), University Hospital Bonn (DE), Manchester Academic Health Science Centre (GB), Hospital Universitario La Paz (ES), University Hospital of Wales (GB), Sahlgrenska University Hospital (SE), University Medical Center Freiburg (DE), German Primate Center (DE), Erasmus MC (NL), University of Manchester (GB), Hospital Universitari i Politècnic La Fe (ES), Henry Royce Institute (GB), Medizinische Hochschule Hannover (DE), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Assistance Publique – Hôpitaux de Paris (FR), Hospital La Paz Institute for Health Research (ES), St Mary's Hospital (GB), Duke Medical Center (US), Fondazione Stella Maris (IT), Hospital Universitario Central de Asturias (ES), Greenwood Genetic Center (US), Genomics (United Kingdom) (GB), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Queen Elizabeth University Hospital (GB), Instituto Nacional de Silicosis (ES), University Hospital Carl Gustav Carus (DE), Centro Neurolesi Bonino Pulejo (IT), Instituto de Investigación Sanitaria del Principado de Asturias (ES), University of Göttingen (DE), University of Hong Kong (HK), Ruhr University Bochum (DE)
National Institute for Health and Care Research, European Commission, Great Ormond Street Hospital Charity, Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Albert-Ludwigs-Universität Freiburg, Technische Universität Dresden, Else Kröner-Fresenius-Stiftung, Fritz Thyssen Stiftung, Medizinischen Hochschule Hannover, Manchester Biomedical Research Centre, Medical Research Council
Openalex Percentile: Top 2%
Genomics and Rare Diseases
30.93
DOIOpen Access PDFOpenAlex
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