Four novel optineurin mutations in patients with sporadic amyotrophic lateral sclerosis in Mainland China

Abstract

This study was to investigate the genetic contribution of optineurin (OPTN), a gene associated with primary open-angle glaucoma and amyotrophic lateral sclerosis (ALS), in Chinese patients with ALS. To gain additional insight into the spectrum and pathogenic relevance of this gene for ALS, we sequenced all the coding exons of OPTN and intron-exon boundaries in 398 patients with ALS [33 familial ALS (FALS), 365 unrelated sporadic ALS (SALS)] using next-generation sequencing. Six nonsynonymous variants were identified in 6 unrelated patients with SALS, in which one patient harbored 2 different OPTN variants and another carried an SETX mutation at the same time. Among those 6 variants, 4 were novel missense mutations: c.247C>T (p.R83C), c.676T>C (p.F226L), c.1699A>G (p.Y567A), and c.1713C>G (p.H571Q) (all heterozygous). The remaining 2 were already reported in previous studies. All 6 patients were spinal onset but showed differences in ALS subtypes as well as age of onset and disease progression. Taken together, we detected 4 novel missense OPTN mutations and 2 previously described mutations that might be causal for ALS, accounting for a mutant frequency of 1.10% (4/365) in patients with SALS after excluding 2 benign variants, and confirmed that OPTN mutations are common in Asian populations. In addition, our data suggested that variability in phenotype of the same mutation might partly be due to the oligogenic basis of ALS.