Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■在肌萎缩侧索硬化症（ALS）患者中已经报道了hnRNPA1的致病变异。然而,关于hnRNPA1突变体谱和变异体致病性的研究很少。
■我们在ALS患者中对ALS相关基因进行了全外显子组测序，并随后验证了hnRNPA1中的罕见变异。回顾了文献中报道的hnRNPA1突变，并结合我们的结果来确定基因型-表型关系。通过将突变体hnRNPA1转染到293T细胞中在体外进行新变体p.G195A的功能分析。
■在招募的207名ALS患者中，确定了3种罕见的hnRNPA1变异（突变频率1.45％），包括两个复发突变(p.P340S和p.G283R)，和一个新颖的罕见变种p.G195A.结合以前的报告，有27例ALS患者鉴定出15例hnRNPA1突变.发病年龄为47.90±1.52岁，以肢为主。p.P340S突变在两个独立的预期寿命延长的家庭中引起连ail臂综合征（FAS）。新发现的p.G195A突变,位于PrLD（“类病毒”域）/LCD（低复杂度域）的开头，导致3D蛋白质预测中的局部结构变化。亚砷酸钠暴露后，突变体hnRNPA1保留在细胞核中，但观察到细胞质G3BP1阳性应激颗粒清除不足。这不同于p.P340S突变,其引起细胞质易位和应激颗粒形成。没有观察到细胞质TDP-43易位。
■在ALS患者中，hnRNPA1的突变总体上是轻微的。p.P340S突变与FAS的表现有关。hnRNPA1的LCD中的突变导致应激颗粒加工错误。
■我们在ALS患者中对ALS相关基因进行了全外显子组测序，并随后验证了hnRNPA1中的罕见变异。回顾了文献中报道的hnRNPA1突变，并结合我们的结果来确定基因型-表型关系。通过将突变体hnRNPA1转染到293T细胞中在体外进行新变体p.G195A的功能分析。
■在招募的207名ALS患者中，确定了3种罕见的hnRNPA1变异（突变频率1.45％），包括两个复发突变(p.P340S和p.G283R)，和一个新颖的罕见变种p.G195A.结合以前的报告，有27例ALS患者鉴定出15例hnRNPA1突变.发病年龄为47.90±1.52岁，以肢为主。p.P340S突变在两个独立的预期寿命延长的家庭中引起连ail臂综合征（FAS）。新发现的p.G195A突变,位于PrLD（“类病毒”域）/LCD（低复杂度域）的开头，导致3D蛋白质预测中的局部结构变化。亚砷酸钠暴露后，突变体hnRNPA1保留在细胞核中，但观察到细胞质G3BP1阳性应激颗粒清除不足。这不同于p.P340S突变,其引起细胞质易位和应激颗粒形成。没有观察到细胞质TDP-43易位。
■在ALS患者中，hnRNPA1的突变总体上是轻微的。p.P340S突变与FAS的表现有关。hnRNPA1的LCD中的突变导致应激颗粒加工错误。
