F45. Genetic analysis of TIA1 gene in Chinese patients with amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive lethal neurodegenerative disorder characterized by affecting the upper and lower motor neurons of the brain, brainstem and spinal cord. Approximately 15% of ALS patients also suffering from frontotemporal dementia (FTD). Very recently, six missense mutations affecting the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) were identified in 1039 non-Hispanic white ALS and ALS-FTD patients. Mutations in the TIA1 gene were suggest to account for ∼2% FALS and <0.5% sporadic ALS (SALS). Those data suggest that TIA1 mutations might be a rare cause of ALS ± FTD. Studies analyzing Asian ALS patient cohorts have not been reported. Previous studies have shown that mutations in the ALS causal genes varied among ethnic populations, such as the G4C2 repeat expansion in the C9orf72 gene is rare in Asian people. To investigate the frequency and spectrum of TIA1 mutations further, we firstly performed mutational screening of TIA1 in a large cohort of ALS/ALS-FTD patients of Chinese origin. The study included 576 Chinese ALS/ALS-FTD patients (FALS = 28; SALS = 535; ALS-FTD = 13) and 500 neurologically normal control subjects. All participants were of Han descent and from mainland China. ALS/ALS-FTD patients were registered at ALS clinic of Neurology Department, Peking Union Medical College Hospital from January 2016 to August 2017. TIA1 (NM_022173) exons 11, 12 and 13 encoding the prion-like LCD domain of TIA1 were sequenced in all 576 cases. Resulting chromatograms were aligned to reference human genome ( UCSC hg19) using CodonCode Aligner tool. All patients harboring mutations of the TIA1 were examined other common ALS causal genes including SOD1, ANXA11, FUS, OPTN, UBQLN2, TARDB and C9orf72. Besides, the identified mutations were subsequently screened in 500 controls. TIA1 sequence analysis revealed a novel heterozygous missense mutation, c.973A>G (p.N325D), in a sporadic ALS case. The variant was not present in our 500 neurologically normal controls as well as several public data bases includingExAC, gnomAD, 1000 Genomes Project and SNP150. The p.N325D substitution affects an highly conserved amino acid in the prion-like LCD domain. Moreover, Four distinct programs – PolyPhen2, Mutation Taster, SIFT and CADD – all predicted p.N325D as a damaging mutation. In conclusion, we have identified a novel mutation in the TIA1 gene in SALS patients of Chinese origin. Our findings provide an overview of the TIA1 mutation in Chinese ALS patients. We propose that the TIA1 mutation is not a frequent mutation in Chinese ALS patients.