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

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)653-660
Number of pages8
JournalHuman mutation
Volume37
Issue number7
DOIs
StatePublished - Jul 1 2016

Keywords

  • CDG
  • asparagine-linked glycosylation protein 1
  • carbohydrate-deficient transferrin
  • xeno-tetrasaccharide

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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