Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. More than 25 ALS-related genes have been identified, accounting for approximately 10% of sporadic ALS (SALS) and two-thirds of familial ALS (FALS) cases. Several recent studies showed that genetic factors might have a larger contribution to young-onset ALS than to ALS cases overall. However, the genetic profile of young-onset ALS patients is not yet fully understood. Here, we investigated a cohort of 27 young-onset ALS patients (onset age < 45 years) through whole-exome sequencing (WES). Genetic analysis identified pathogenic variants of FUS (25.9%), SOD1 (22.2%), TARDBP (3.7%), and VCP (3.7%) in 27 young-onset ALS patients. Of 12 identified types of mutations, c.1528A > C in FUS and c.266G > A in VCP were novel. All of the cases in this study reflect a monogenic origin with an autosomal dominant mode of inheritance. Notably, a novel de novo missense mutation, c.1528A > C (p.K510Q), in FUS was identified in a 29-year-old ALS patient. Expression of the K510Q mutant FUS resulted in cytoplasmic mislocalization of FUS in cultured cells and induced neural toxicity in a fly model. This study provides further evidence of the genetic profile of young-onset ALS patients from China and expands the mutational spectrum of the FUS gene, with one new K510Q mutation identified.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the upper and lower motor neurons of the brain and spinal cord, mainly characterized by weakness, muscle atrophy, dysarthria, and breathing difficulties (Rowland and Shneider, 2001)
We evaluated the frequency of pathogenic variants in ALS-associated genes in young-onset Chinese patients
superoxide dismutase 1 (SOD1) was the most frequently mutated gene in familial young-onset ALS patients, while the fused in sarcoma (FUS) gene was the most frequently mutated in sporadic young-onset ALS patients
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the upper and lower motor neurons of the brain and spinal cord, mainly characterized by weakness, muscle atrophy, dysarthria, and breathing difficulties (Rowland and Shneider, 2001). Since superoxide dismutase 1 (SOD1) was reported as the first ALS-associated gene in 1993 (Rosen et al, 1993), more than 25 genes have been described to be associated with ALS, Mutations in Young-Onset ALS including TAR DNA-binding protein 43 (TARDBP), fused in sarcoma (FUS), valosin-containing protein (VCP), and C9ORF72 (Nguyen et al, 2018). Mutations in these genes have been identified in approximately two-thirds of familial ALS (FALS) and 10% of sporadic ALS (SALS) cases (Chia et al, 2018). While mutations of SOD1 were the most frequent in FALS (30.6%), mutations were second-most frequent (5.6%) in FUS, and this was the most abundant mutation in SALS (1.7%) (Liu et al, 2016)
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