Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation.

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

Document Type

Article

Publication Date

7-22-2021

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

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

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

34291734

Language

English