DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM
DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM
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 ribonucleoproteins. hnRNPs are a major subclass of evolutionarily conserved RBPs that are primarily concentrated in the nucleus and are heavily involved in pre-mRNA splicing, mRNA stability and transcriptional/translational regulation. During times of stress, standard translational programming is interrupted, and hnRNPs, mRNA, and other RBPs condense in the cytoplasm, forming liquid-liquid phase separated (LLPS) membraneless organelles termed stress granules (SGs). SGs are central to the pathogenesis of (neuro-)degenerative diseases, including ALS and inclusion body myopathy (IBM). hnRNPs and other RBPs are critical components of SGs. Indeed, the link between SGs, hnRNPs, and neurodegenerative diseases has been established by the identification of additional mutations in RBPs that affect SG biology, including FUS, TDP-43, hnRNPA1, hnRNPA2B1, and TIA1, each of which can directly lead to ALS, IBM and other related neurodegenerative diseases. Here, we report and characterize four novel HNRNPA1 mutations and two known HNRNPA1 mutations, previously reported as being causal for ALS, in a broad spectrum of patients with hereditary motor neuropathy (HMN), ALS, and myopathy. Our results show the different effects of mutations on hnRNPA1 fibrillization, liquid-liquid phase separation, and SG dynamics, indicating the possibility of different underlying pathomechanisms for HNRNPA1 mutations with a possible link to the clinical phenotypes.
Taylor JP、Shorter J、Drake LE、Voermans NC、Wheeler MT、Van Schil K、Fare CM、Ford AF、Kocha¨?ski A、Van den Bergh P、Bonner D、Mehrabyan A、Lemmers RJLF、Beijer D、van der Maarel SM、Deconinck T、Guo L、Baets J、O?ˉDonovan K、De Jonghe P、Palmer S、Sampson JB、Dubuisson N、Kabzi¨?ska D、Mademan I、Kim HJ
Department of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital||Howard Hughes Medical InstituteDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical CenterStanford Center for Undiagnosed Diseases, Stanford UniversityCenter of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43Department of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaDepartment of Biochemistry and Biophysics, Perelman School of Medicine, University of PennsylvaniaNeuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of SciencesNeuromuscular Reference Centre, University Hospitals St-Luc, University of LouvainStanford Center for Undiagnosed Diseases, Stanford UniversityDepartment of Neurology, University of North Carolina at Chapel HillDepartment of Human Genetics, Leiden University Medical CenterTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp||Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of AntwerpDepartment of Human Genetics, Leiden University Medical CenterCenter of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania||Department of Biochemistry and Molecular Biology, Thomas Jefferson UniversityTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp||Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp||Neuromuscular Reference Centre, Department of Neurology, Antwerp University HospitalDepartment of Cell and Molecular Biology, St. Jude Children?ˉs Research HospitalTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp||Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp||Neuromuscular Reference Centre, Department of Neurology, Antwerp University HospitalDepartment of Neurology, University of North Carolina at Chapel HillStanford Center for Undiagnosed Diseases, Stanford UniversityNeuromuscular Reference Centre, University Hospitals St-Luc, University of LouvainNeuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of SciencesTranslational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp||Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of AntwerpDepartment of Cell and Molecular Biology, St. Jude Children?ˉs Research Hospital
神经病学、精神病学基础医学分子生物学
heterogeneous nuclear ribonucleoproteinneurodegenerationself-fibrillizationstress granulesnext-generation sequencing
Taylor JP,Shorter J,Drake LE,Voermans NC,Wheeler MT,Van Schil K,Fare CM,Ford AF,Kocha¨?ski A,Van den Bergh P,Bonner D,Mehrabyan A,Lemmers RJLF,Beijer D,van der Maarel SM,Deconinck T,Guo L,Baets J,O?ˉDonovan K,De Jonghe P,Palmer S,Sampson JB,Dubuisson N,Kabzi¨?ska D,Mademan I,Kim HJ.DEFINING THE DIVERSITY OF HNRNPA1 MUTATIONS IN CLINICAL PHENOTYPE AND PATHOMECHANISM[EB/OL].(2025-03-28)[2025-06-08].https://www.medrxiv.org/content/10.1101/2021.02.02.21250330.点此复制
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