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ALG1‐CDG: Clinical and Molecular Characterization of 39 Unreported Patients
Author(s) -
Ng Bobby G.,
Shiryaev Sergey A.,
Rymen Daisy,
Eklund Erik A.,
Raymond Kimiyo,
Kircher Martin,
Abdenur Jose E.,
Alehan Fusun,
Midro Alina T.,
Bamshad Michael J.,
Barone Rita,
Berry Gerard T.,
Brumbaugh Jane E.,
Buckingham Kati J.,
Clarkson Katie,
Cole F. Sessions,
O'Connor Shawn,
Cooper Gregory M.,
Coster Rudy,
Demmer Laurie A.,
Diogo Luisa,
Fay Alexander J.,
Ficicioglu Can,
Fiumara Agata,
Gahl William A.,
Ganetzky Rebecca,
Goel Himanshu,
Harshman Lyndsay A.,
He Miao,
Jaeken Jaak,
James Philip M.,
Katz Daniel,
Keldermans Liesbeth,
Kibaek Maria,
Kornberg Andrew J.,
Lachlan Katherine,
Lam Christina,
YaplitoLee Joy,
Nickerson Deborah A.,
Peters Heidi L.,
Race Valerie,
Régal Luc,
Rush Jeffrey S.,
Rutledge S. Lane,
Shendure Jay,
Souche Erika,
Sparks Susan E.,
Trapane Pamela,
SanchezValle Amarilis,
Vilain Eric,
Vøllo Arve,
Waechter Charles J.,
Wang Raymond Y.,
Wolfe Lynne A.,
Wong Derek A.,
Wood Tim,
Yang Amy C.,
Matthijs Gert,
Freeze Hudson H.
Publication year - 2016
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22983
Subject(s) - biology , glycosylation , biomarker , phenotype , mutation , dolichol , gene , compound heterozygosity , genetics , glycoprotein , mannose , biochemistry , biosynthesis
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‐GlcNAc 2 , 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.