Xinyi Zhang, Ye Sun, Xinzhe Zhang, Dongchao Shen, Shi Shu, Xunzhe Yang, Mingsheng Liu, Liying Cui, Qing Liu, Xue Zhang
{"title":"Genotype-phenotype association and functional analysis of <i>hnRNPA1</i> mutations in amyotrophic lateral sclerosis.","authors":"Xinyi Zhang, Ye Sun, Xinzhe Zhang, Dongchao Shen, Shi Shu, Xunzhe Yang, Mingsheng Liu, Liying Cui, Qing Liu, Xue Zhang","doi":"10.1080/21678421.2024.2346502","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Pathogenic variants in <i>hnRNPA1</i> have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on <i>hnRNPA1</i> mutant spectrum and pathogenicity of variants were rare.</p><p><strong>Methods: </strong>We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in <i>hnRNPA1</i> in our ALS patients. The <i>hnRNPA1</i> mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant <i>hnRNPA1</i> into 293T cell.</p><p><strong>Results: </strong>Among 207 ALS patients recruited, 3 rare <i>hnRNPA1</i> variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 <i>hnRNPA1</i> mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD (\"prion-like\" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.</p><p><strong>Conclusion: </strong>Mutations in <i>hnRNPA1</i> are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of <i>hnRNPA1</i> cause stress granule misprocessing.</p>","PeriodicalId":72184,"journal":{"name":"Amyotrophic lateral sclerosis & frontotemporal degeneration","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Amyotrophic lateral sclerosis & frontotemporal degeneration","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/21678421.2024.2346502","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/8 0:00:00","PubModel":"Epub","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Pathogenic variants in hnRNPA1 have been reported in amyotrophic lateral sclerosis (ALS) patients. However, studies on hnRNPA1 mutant spectrum and pathogenicity of variants were rare.
Methods: We performed whole exome sequencing of ALS-associated genes and subsequent verification of rare variants in hnRNPA1 in our ALS patients. The hnRNPA1 mutations reported in literature were reviewed and combined with our results to determine the genotype-phenotype relationship. Functional analysis of the novel variant p.G195A was performed in vitro by transfection of mutant hnRNPA1 into 293T cell.
Results: Among 207 ALS patients recruited, 3 rare hnRNPA1 variants were identified (mutant frequency 1.45%), including two recurrent mutations (p.P340S and p.G283R), and a novel rare variant p.G195A. In combination with previous reports, there are 27 ALS patients with 15 hnRNPA1 mutations identified. Disease onset age was 47.90 ± 1.52 years with predominant limb onset. The p.P340S mutation caused flail arm syndrome (FAS) in two independent families with extended life expectancy. The newly identified p.G195A mutation, lying at the start of the PrLD ("prion-like" domain)/LCD (low-complexity domain), causes local structural changes in 3D protein prediction. Upon sodium arsenite exposure, mutant hnRNPA1 retained in the nucleus but deficit of cytoplasmic G3BP1-positive stress granule clearance was observed. This is different from the p.P340S mutation which caused both cytoplasmic translocation and stress granule formation. No cytoplasmic TDP-43 translocation was observed.
Conclusion: Mutations in hnRNPA1 are overall minor in ALS patients. The p.P340S mutation is associated with manifestation of FAS. Mutations in LCD of hnRNPA1 cause stress granule misprocessing.