학술논문
Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation
Document Type
article
Author
Danique Beijer; Hong Joo Kim; Lin Guo; Kevin O’Donovan; Inès Mademan; Tine Deconinck; Kristof Van Schil; Charlotte M. Fare; Lauren E. Drake; Alice F. Ford; Andrzej Kochański; Dagmara Kabzińska; Nicolas Dubuisson; Peter Van den Bergh; Nicol C. Voermans; Richard J.L.F. Lemmers; Silvère M. van der Maarel; Devon Bonner; Jacinda B. Sampson; Matthew T. Wheeler; Anahit Mehrabyan; Steven Palmer; Peter De Jonghe; James Shorter; J. Paul Taylor; Jonathan Baets
Source
JCI Insight, Vol 6, Iss 14 (2021)
Subject
Language
English
ISSN
2379-3708
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.