Genetic and Functional Analysis of Glycosyltransferase 8 Domain-Containing Protein 1 in Taiwanese Patients With Amyotrophic Lateral Sclerosis

To investigate the frequency, spectrum, and molecular functional effect of glycosyltransferase 8 domain-containing protein 1 (GLT8D1) variations in Taiwanese patients with amyotrophic lateral sclerosis (ALS). We performed genetic analyses of in 410 unrelated patients with ALS by Sanger sequencing. The 410 patients were selected from a cohort of 477 unrelated patients with ALS after excluding variations in common ALS disease genes. Functional effects of the variation were investigated by in vitro functional analysis. We identified a novel heterozygous missense variation in , p.I290M (c.870C>G), in 1 single patient with familial ALS. The patient with the p.I290M variation had a spinal-onset ALS with disease onset at age 60 years and a survival of 6 years. Functional studies demonstrated that the variant I290M GLT8D1 protein was mislocalized to the endoplasmic reticulum (ER), provoked ER stress and unfolded protein response, compromised the glycosyltransferase activity, and led to an increased cytotoxicity. variations account for 0.2% (1/477) of the patients with ALS in Taiwan. These findings expand the spectrum of variation and support the pathogenic role of variations in ALS.