Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis

Abstract

Highlights d ALS-causing mutations found within the gene encoding the glycosyltransferase GLT8D1 d Five ALS-associated GLT8D1 mutations proximate to the substrate binding site d GLT8D1 mutations exhibit in vitro cytotoxicity and impair enzyme activity d GLT8D1 mutations induce motor deficits in zebrafish consistent with ALS

Mutation screening and burden analysis of GLT8D1 in Chinese patients with ALS

“…The pedigree validation of the fALS patient carrying p.V291I was not available because the patient's affected family member has died. The variant p.G78A co-segregated with ALS between a proband and his mother (PP1); moreover, only mutations in the exon 4 were considered as pathogenic [6] (PM1); furthermore, p.G78A was absent in the East Asian controls (PM2) but altered the amino acid residue at the same position as the variant-p.G78W, which has been reported to be pathogenic by the previous study [6] To further evaluate the accumulated association of the rare variants in GLT8D1 with ALS, we did whole-gene level and exon 4 speci c rare variants burden analyses in sporadic cases. In the whole gene level, together with previous study from China mainland [7], there were totally 4 rare variants (5 alleles) among the 1410 sALS (2820 alleles); while there were 25 variants (54 alleles) ful lled the same criteria among 9766 cases (19532 alleles) in the gnomAD East Asian controls.…”

“…In recent years, with the development of gene sequencing methods and bioinformatic tools, an increasing number of novel ALS causative genes have been identi ed. A missense mutation p.R92W located in the exon 4 of glycosyltransfersase 8 domain containing 1 gene (GLT8D1) was found to co-segregate with ALS in an autosomal dominant ALS family [6]. Furthermore, 5 additional rare deleterious mutations in the same exon were also identi ed in 14 ALS cases, which implied that the rare deleterious variants affecting conserved amino acids in exon 4 of GLT8D1 were signi cantly enriched in ALS patients [6].…”

“…Furthermore, 5 additional rare deleterious mutations in the same exon were also identi ed in 14 ALS cases, which implied that the rare deleterious variants affecting conserved amino acids in exon 4 of GLT8D1 were signi cantly enriched in ALS patients [6]. Functional studies found overexpression of mutant GLT8D1 (p.R92W and p.G78W) decreased the enzyme activity which lead to in vitro cytotoxicity and induced motor de cits in zebra sh consistent with ALS [6]. Thus, GLT8D1 gene de ned as a novel ALS causative gene in 2019 [6].…”

“…Functional studies found overexpression of mutant GLT8D1 (p.R92W and p.G78W) decreased the enzyme activity which lead to in vitro cytotoxicity and induced motor de cits in zebra sh consistent with ALS [6]. Thus, GLT8D1 gene de ned as a novel ALS causative gene in 2019 [6]. However, in a subsequent replication study conducted in a cohort of 512 ALS patients from Southeast of China failed to identify any rare variant in the exon 4 of GLT8D1 [7].…”

“…A missense mutation p.R92W located in the exon 4 of glycosyltransfersase 8 domain containing 1 gene (GLT8D1) was found to co-segregate with ALS in an autosomal dominant ALS family [6]. Furthermore, 5 additional rare deleterious mutations in the same exon were also identi ed in 14 ALS cases, which implied that the rare deleterious variants affecting conserved amino acids in exon 4 of GLT8D1 were signi cantly enriched in ALS patients [6]. Functional studies found overexpression of mutant GLT8D1 (p.R92W and p.G78W) decreased the enzyme activity which lead to in vitro cytotoxicity and induced motor de cits in zebra sh consistent with ALS [6].…”