Kuang Lisha, Kamelgarn Marisa, Arenas Alexandra, Gal Jozsef, Taylor Deborah, Gong Weiming, Brown Martin, St Clair Daret, Kasarskis Edward J, Zhu Haining
Molecular and Cellular Biochemistry (L.K., J.G., H.Z.), Department of Toxicology and Cancer Biology (M.K., A.A., D.S.C., H.Z.), and Department of Neurology (D.T., E.J.K.), College of Medicine, University of Kentucky, Lexington; Hefei National Laboratory for Physical Sciences at the Microscale (W.G.), University of Science and Technology of China, Anhui; Department of Neurology (M.B.), University of Louisville; and Research and Development (E.J.K., H.Z.), Lexington VA Medical Center, KY.
Neurol Genet. 2017 Jul 20;3(4):e172. doi: 10.1212/NXG.0000000000000172. eCollection 2017 Aug.
To describe the clinical features of a novel fused in sarcoma (FUS) mutation in a young adult female amyotrophic lateral sclerosis (ALS) patient with rapid progression of weakness and to experimentally validate the consequences of the P525R mutation in cellular neuronal models.
We conducted sequencing of genomic DNA from the index patient and her family members. Immunocytochemistry was performed in various cellular models to determine whether the newly identified P525R mutant FUS protein accumulated in cytoplasmic inclusions. Clinical features of the index patient were compared with 19 other patients with ALS carrying the P525L mutation in the same amino acid position.
A novel mutation c.1574C>G (p.525P>R) in the gene was identified in the index patient. The clinical symptoms are similar to those in familial ALS patients with the P525L mutation at the same position. The P525R mutant FUS protein showed cytoplasmic localization and formed large stress granule-like cytoplasmic inclusions in multiple cellular models.
The clinical features of the patient and the cytoplasmic inclusions of the P525R mutant FUS protein strengthen the notion that mutations at position 525 of the FUS protein result in a coherent phenotype characterized by juvenile or young adult onset, rapid progression, variable positive family history, and female preponderance.
描述一名年轻成年女性肌萎缩侧索硬化症（ALS）患者中一种新的肉瘤融合基因（FUS）突变的临床特征，该患者肌无力进展迅速，并在细胞神经元模型中通过实验验证P525R突变的后果。
我们对索引患者及其家庭成员的基因组DNA进行了测序。在各种细胞模型中进行免疫细胞化学，以确定新鉴定的P525R突变型FUS蛋白是否在细胞质包涵体中积累。将索引患者的临床特征与其他19名在相同氨基酸位置携带P525L突变的ALS患者进行比较。
在索引患者中鉴定出该基因中的一种新突变c.1574C>G（p.525P>R）。临床症状与在相同位置携带P525L突变的家族性ALS患者相似。P525R突变型FUS蛋白在多种细胞模型中表现出细胞质定位，并形成大的应激颗粒样细胞质包涵体。
患者的临床特征以及P525R突变型FUS蛋白的细胞质包涵体强化了这样一种观点，即FUS蛋白第525位的突变导致一种连贯的表型，其特征为青少年或年轻成人发病、进展迅速、家族史阳性情况不一以及女性占优势。
