Portal de investigación
Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies
Fecha de publicación:
Fecha Ahead of Print:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Di Donato, N.
- Thom, A.
- Rump, A.
- Greve, J.N.
- Cadiñanos, J.
- Calabrò, R.S.
- Cathey, S.
- Chung, B.
- Cope, H.
- Costales-Marcos, M.
- Cuvertino, S.
- Dinkel, P.
- Erripi, K.
- Fry, A.E.
- Garavelli, L.
- Hoffjan, S.
- Janzarik, W.G.
- Kreimer, I.
- Mancini, G.
- Meinhardt, A.
- Niehaus, I.
- Pilz, D.
- Ricca, I.
- Simarro, F.S.
- Schröck, E.
- Marquardt, A.
- Taft, M.H.
- Tezcan, K.
- Thunström, S.
- Verhagen, J.
- Verloès, A.
- Wollnik, B.
- Krawitz, P.
- Hsieh, T.-C.
- Seifert, M.
- Heide, M.
- Lawrence, C.B.
- Neil A. Roberts, N.A.
- Manstein, D.J.
- Woolf, A.S.
- Banka, S.
Grupos
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. © 2025 The Authors.
Datos de la publicación
- ISSN/ISSNe:
- 0002-9297, 1537-6605
- Tipo:
- Article
- Páginas:
- 324-341
- PubMed:
- 41529692
- Enlace a otro recurso:
- www.scopus.com
- Factor de Impacto:
- 5,042 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
AMERICAN JOURNAL OF HUMAN GENETICS CELL PRESS
Citas Recibidas en Web of Science: 2
Documentos
- No hay documentos
Filiaciones
Keywords
- beta actin; actin; isoprotein; ACTB gene; ACTG1 gene; actin polymerization; adolescent; adult; animal cell; Article; child; cohort analysis; controlled study; depolymerization; diagnostic test accuracy study; disease association; disease severity; female; frameshift mutation; gene; genetic disorder; genotype phenotype correlation; human; human cell; human genetics; infant; major clinical study; male; missense mutation; molecular biology; molecular pathology; neuronal migration disorder; nonhuman; nonmuscle actinopathy; nonsense mutation; protein degradation; allele; genetic association study; genetics; metabolism; phenotype; Actins; Alleles; Genetic Association Studies; Humans; Mutation, Missense; Phenotype; Protein Isoforms
Cita
Di N,Thom A,Rump A,Greve JN,Cadiñanos J,Calabrò RS,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,MARÍN P,Meinhardt A,Niehaus I,Pilz D,Ricca I,Simarro FS,Schröck E,Marquardt A,Taft MH,Tezcan K,Thunström S,Verhagen J,Verloès A,Wollnik B,Krawitz P,Hsieh T-C,Seifert M,Heide M,Lawrence CB,Neil A. Roberts NA,Manstein DJ,Woolf AS,Banka S. Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies. Am. J. Hum. Genet. 2026. 113. (2):p. 324-341. IF:7,700. (1).