PT  - JOURNAL ARTICLE
AU  - Tsai, Pei-Chien
AU  - Jih, Kang-Yang
AU  - Shen, Ting-Yi
AU  - Liu, Yi-Hong
AU  - Lin, Kon-Ping
AU  - Liao, Yi-Chu
AU  - Lee, Yi-Chung
TI  - Genetic and Functional Analysis of Glycosyltransferase 8 Domain–Containing Protein 1 in Taiwanese Patients With Amyotrophic Lateral Sclerosis
AID  - 10.1212/NXG.0000000000000627
DP  - 2021 Dec 01
TA  - Neurology Genetics
PG  - e627
VI  - 7
IP  - 6
4099  - http://ng.neurology.org/content/7/6/e627.short
4100  - http://ng.neurology.org/content/7/6/e627.full
SO  - Neurol Genet2021 Dec 01; 7
AB  - Background and Objectives 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).Methods We performed genetic analyses of GLT8D1 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 GLT8D1 variation were investigated by in vitro functional analysis.Results We identified a novel heterozygous missense variation in GLT8D1, 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.Discussion GLT8D1 variations account for 0.2% (1/477) of the patients with ALS in Taiwan. These findings expand the spectrum of GLT8D1 variation and support the pathogenic role of GLT8D1 variations in ALS.ALS=amyotrophic lateral sclerosis; C9ORF72=chromosome 9 open reading frame 72; CCK-8=cell counting kit-8; ER=endoplasmic reticulum; FUS=fused in sarcoma; GLT8D1=glycosyltransferase 8 domain-containing protein 1; gnomAD=genome aggregation database; LDH=lactate dehydrogenase; MPZ=myelin protein zero; RT-qPCR=real-time quantitative PCR; SOD1=superoxide dismutase 1; sXBP1=spliced X-box–binding protein 1; TARDBP=TAR DNA-binding protein; TBK1=TANK-binding kinase 1; UPR=unfolded protein response; WT=wild-type