ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

TitleALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
Publication TypeJournal Article
Year of Publication2016
AuthorsNg, BG, Shiryaev, SA, Rymen, D, Eklund, EA, Raymond, K, Kircher, M, Abdenur, JE, Alehan, F, Midro, AT, Bamshad, MJ, Barone, R, Berry, GT, Brumbaugh, JE, Buckingham, KJ, Clarkson, K, F Cole, S, O'Connor, S, Cooper, GM, Van Coster, R, Demmer, LA, Diogo, L, Fay, AJ, Ficicioglu, C, Fiumara, A, Gahl, WA, Ganetzky, R, Goel, H, Harshman, LA, He, M, Jaeken, J, James, PM, Katz, D, Keldermans, L, Kibaek, M, Kornberg, AJ, Lachlan, K, Lam, C, Yaplito-Lee, J, Nickerson, DA, Peters, HL, Race, V, Régal, L, Rush, JS, S Rutledge, L, Shendure, J, Souche, E, Sparks, SE, Trapane, P, Sanchez-Valle, A, Vilain, E, Vøllo, A, Waechter, CJ, Wang, RY, Wolfe, LA, Wong, DA, Wood, T, Yang, AC, Matthijs, G, Freeze, HH
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalHum Mutat
Date Published2016 07
KeywordsBiomarkers, Congenital Disorders of Glycosylation, Female, Genes, Lethal, Glycosylation, Humans, Male, Mannosyltransferases, Mutation, Polysaccharides, Sequence Analysis, DNA, Survival Analysis

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

Alternate JournalHum. Mutat.
PubMed ID26931382
PubMed Central IDPMC4907823
Grant ListT32 GM008638 / GM / NIGMS NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
U01 HG007301 / HG / NHGRI NIH HHS / United States
R01 DK055615 / DK / NIDDK NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 GM102129 / GM / NIGMS NIH HHS / United States
R01 DK099551 / DK / NIDDK NIH HHS / United States