Authors
Danique Beijer, Translational Neurosciences, Faculty of Medicine and Health Sciences, and Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium
Hong Joo Kim, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Lin Guo, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USAFollow
Kevin O'Donovan, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
Inès Mademan, Translational Neurosciences, Faculty of Medicine and Health Sciences, and Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium
Tine Deconinck, Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium
Kristof Van Schil, Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium
Charlotte M Fare, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Lauren E Drake, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Alice F Ford, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Andrzej Kochański, Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Dagmara Kabzińska, Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
Nicolas Dubuisson, Neuromuscular Reference Centre, University Hospitals St-Luc, University of Louvain, Brussels, Belgium
Peter Van den Bergh, Neuromuscular Reference Centre, University Hospitals St-Luc, University of Louvain, Brussels, Belgium
Nicol C Voermans, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
Richard Jlf Lemmers, Human Genetics Department, Leiden University Medical Center, Netherlands
Silvère M van der Maarel, Human Genetics Department, Leiden University Medical Center, Netherlands
Devon Bonner, Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA
Jacinda B Sampson, Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA
Matthew T Wheeler, Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, California, USA
Anahit Mehrabyan, Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Steven Palmer, Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Peter De Jonghe, Translational Neurosciences, Faculty of Medicine and Health Sciences, and Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Wilrijk, Belgium
James Shorter, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
J Paul Taylor, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA; Howard Hughes Medical Institute, Chevy Chase, Maryland, USA
Jonathan Baets, Translational Neurosciences, Faculty of Medicine and Health Sciences, and Laboratory for Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Wilrijk, Belgium; Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Wilrijk, Belgium
Publication Date
7-22-2021
Abstract
Mutations in HNRNPA1 encoding heterogeneous nuclear ribonucleoprotein (hnRNP) A1 are a rare cause of amyotrophic lateral sclerosis (ALS) and multisystem proteinopathy (MSP). hnRNPA1 is part of the group of RNA-binding proteins (RBPs) that assemble with RNA to form RNPs. hnRNPs are concentrated in the nucleus and function in pre-mRNA splicing, mRNA stability, and the regulation of transcription and translation. During stress, hnRNPs, mRNA, and other RBPs condense in the cytoplasm to form stress granules (SGs). SGs are implicated in the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). Mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, underlie ALS, IBM, and other neurodegenerative diseases. Here, we characterize 4 potentially novel HNRNPA1 mutations (yielding 3 protein variants: *321Eext*6, *321Qext*6, and G304Nfs*3) and 2 known HNRNPA1 mutations (P288A and D262V), previously connected to ALS and MSP, in a broad spectrum of patients with hereditary motor neuropathy, ALS, and myopathy. We establish that the mutations can have different effects on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics. P288A accelerated fibrillization and decelerated SG disassembly, whereas *321Eext*6 had no effect on fibrillization but decelerated SG disassembly. By contrast, G304Nfs*3 decelerated fibrillization and impaired liquid phase separation. Our findings suggest different underlying pathomechanisms for HNRNPA1 mutations with a possible link to clinical phenotypes.
Recommended Citation
Beijer, Danique; Kim, Hong Joo; Guo, Lin; O'Donovan, Kevin; Mademan, Inès; Deconinck, Tine; Van Schil, Kristof; Fare, Charlotte M; Drake, Lauren E; Ford, Alice F; Kochański, Andrzej; Kabzińska, Dagmara; Dubuisson, Nicolas; Van den Bergh, Peter; Voermans, Nicol C; Lemmers, Richard Jlf; van der Maarel, Silvère M; Bonner, Devon; Sampson, Jacinda B; Wheeler, Matthew T; Mehrabyan, Anahit; Palmer, Steven; De Jonghe, Peter; Shorter, James; Taylor, J Paul; and Baets, Jonathan, "Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation." (2021). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 188.
https://jdc.jefferson.edu/bmpfp/188
Comments
This article is the author's final published version in JCI Insight, Volume 6, Issue 14, July 2021
The published version is available at https://doi.org/10.1172/jci.insight.148363
Copyright 2021, Beijer et al.
This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License