ALG1-CDG

Clinical and Molecular Characterization of 39 Unreported Patients

University of Washington Center for Mendelian Genomics

Research output: Contribution to journalArticle

11 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Congenital Disorders of Glycosylation
Mutation
Glycosylation
Biomarkers
Mannosyltransferases
Dolichol
Mannose
Virulence
Proteins
Yeasts
Phenotype
Lipids
Growth
Genes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

University of Washington Center for Mendelian Genomics (2016). ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients. Human mutation, 37(7), 653-660. https://doi.org/10.1002/humu.22983

ALG1-CDG : Clinical and Molecular Characterization of 39 Unreported Patients. / University of Washington Center for Mendelian Genomics.

In: Human mutation, Vol. 37, No. 7, 01.07.2016, p. 653-660.

Research output: Contribution to journalArticle

University of Washington Center for Mendelian Genomics 2016, 'ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients', Human mutation, vol. 37, no. 7, pp. 653-660. https://doi.org/10.1002/humu.22983
University of Washington Center for Mendelian Genomics. ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients. Human mutation. 2016 Jul 1;37(7):653-660. https://doi.org/10.1002/humu.22983
University of Washington Center for Mendelian Genomics. / ALG1-CDG : Clinical and Molecular Characterization of 39 Unreported Patients. In: Human mutation. 2016 ; Vol. 37, No. 7. pp. 653-660.
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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.",
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AU - Jaeken, Jaak

AU - James, Philip M.

AU - Katz, Daniel

AU - Keldermans, Liesbeth

AU - Kibaek, Maria

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AU - Yaplito-Lee, Joy

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KW - CDG

KW - xeno-tetrasaccharide

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