Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation
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 th...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.148363 |
| _version_ | 1811227779950182400 |
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| 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 |
| author_facet | 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 |
| author_sort | Danique Beijer |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T09:46:29Z |
| format | Article |
| id | doaj.art-47cf72fa59a4478a90634b78aa5718fd |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-12T09:46:29Z |
| publishDate | 2021-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-47cf72fa59a4478a90634b78aa5718fd2022-12-22T03:37:55ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-07-01614Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentationDanique BeijerHong Joo KimLin GuoKevin O’DonovanInès MademanTine DeconinckKristof Van SchilCharlotte M. FareLauren E. DrakeAlice F. FordAndrzej KochańskiDagmara KabzińskaNicolas DubuissonPeter Van den BerghNicol C. VoermansRichard J.L.F. LemmersSilvère M. van der MaarelDevon BonnerJacinda B. SampsonMatthew T. WheelerAnahit MehrabyanSteven PalmerPeter De JongheJames ShorterJ. Paul TaylorJonathan BaetsMutations 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.https://doi.org/10.1172/jci.insight.148363GeneticsNeuroscience |
| spellingShingle | 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 Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation JCI Insight Genetics Neuroscience |
| title | Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| title_full | Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| title_fullStr | Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| title_full_unstemmed | Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| title_short | Characterization of HNRNPA1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| title_sort | characterization of hnrnpa1 mutations defines diversity in pathogenic mechanisms and clinical presentation |
| topic | Genetics Neuroscience |
| url | https://doi.org/10.1172/jci.insight.148363 |
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