Genomic and biological panoramas of non-muscle actinopathies
Year: 2024
Type: preprint
Study design: Observational Study
Abstract: Background Cytoskeletal non-muscle actin isoforms are the most abundant intracellular proteins and extensively interact with other molecules. Biological consequences and genotype-phenotype correlations of the variants in genes encoding these isoforms, ACTB and ACTG1, are not delineated. Methods Clinical data analysis from 290 individuals with pathogenic ACTB/ACTG1 variants; characterization of patient cells, mutant proteins, patient-derived iPSC-based models and mutant mice. Results We show that ACTB and ACTG1 variants have distinct clinical profiles. ACTB nonsense, frameshift and missense variants that lead to rapid protein degradation result in milder phenotypes. Heterozygous Actb knockout causes altered neuronal cell morphology and abnormal expression of actin-related genes in newborn mouse brains. Truncating ACTG1 variants are likely to be non-pathogenic, but chromosomal deletions encompassing ACTG1 and flanking genes may result in susceptibility to neurodevelopmental phenotypes. Subsets of disease-causing ACTB missense variants (MVs) result in more severe Type 1 Baraitser-Winter Cerebrofrontofacial (BWCFF1) or Deafness Dystonia syndromes. Pathogenic ACTG1 MVs cause BWCFF2 or isolated hearing loss. These amino acid substitutions are associated with dramatically dysregulated actin polymerization and depolymerization dynamics and, in induced pluripotent stem cells (iPSC) derived models, lead to neuronal migration defects. A significant subset of MVs result in disorders that cannot yet be classified into recognizable groups. Conclusions ACTB or ACTG1 variants and result in minimum eight mechanistically diverse non-muscle actinopathies. These results will improve their diagnosis and management, and pave the way for new treatment strategies. This study reflects the scale of collaborative clinical studies and multi-modal mechanistic studies required to dissect rare allelic disorders.
Source: medRxiv
Authors: Nataliya Di Donato, Andrew Thom, Andreas Rump, Johannes N. Greve, Marcus Kropp, Juan Cadiñanos, Salvatore Calabro, Sara Cathey, Brian Chung, Heidi Cope, Maria Costales, Sara Cuvertino, Philine Dinkel, Kalliopi Erripi, Andrew E. Fry, Livia Garavelli, Kaomei Guan, Sabine Hoffjan, Wibke G. Janzarik, Matti Koenig, Insa Kreimer, Karolina Kuenzel, 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, Leo Zeef, Michael Seifert, Michael Heide, Catherine B. Lawrence, Neil Roberts, Dietmar Manstein, Adrian S. Woolf, Siddharth Banka
Institutions: Technische Universität Dresden, University of Manchester, Medizinische Hochschule Hannover, University of Messina, Azienda Ospedaliera Universitaria Policlinico "G. Martino", Greenwood Genetic Center, University of Hong Kong, Duke Medical Center, Hospital Universitario Central de Asturias, University of Gothenburg, University Hospital of Wales, Azienda Sanitaria Unità Locale di Reggio Emilia, Ruhr University Bochum, University of Freiburg, Erasmus MC, Hospital Universitari i Politècnic La Fe, Queen Elizabeth University Hospital, Fondazione Stella Maris, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research, Kaiser Permanente, Sahlgrenska University Hospital, Universitätsmedizin Göttingen, University of Bonn, German Primate Center, Manchester Academic Health Science Centre
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4401767006