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ALG1-CDG: clinical and molecular characterization of 39 unreported patients

ALG1-CDG: clinical and molecular characterization of 39 unreported patients
ALG1-CDG: clinical and molecular characterization of 39 unreported patients
Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred 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 (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six 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 twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.
cdg, asparagine-linked glycosylation protein 1, carbohydrate-deficient transferrin, xeno-tetrasaccharide
1059-7794
653-660
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Sanchez-Valle, Amarilis
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Vilain, Eric
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Yang, Amy C.
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Matthijs, Gert
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Freeze, Hudson H.
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Rymen, Daisy
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Eklund, Erik A.
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Raymond, Kimiyo
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Kircher, Martin
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Abdenur, Jose E.
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Alehan, Fusun
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Midro, Alina T.
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Gahl, William A.
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He, Miao
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Wong, Derek A.
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Wood, Tim
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Yang, Amy C.
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Matthijs, Gert
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Freeze, Hudson H.
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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., Van 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, Yaplito-Lee, 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, Sanchez-Valle, Amarilis, Vilain, Eric, Vøllo, Arve, Waechter, Charles J., Wang, Raymond Y., Wolfe, Lynne A., Wong, Derek A., Wood, Tim, Yang, Amy C., Matthijs, Gert and Freeze, Hudson H. (2016) ALG1-CDG: clinical and molecular characterization of 39 unreported patients. Human Mutation, 37 (7), 653-660. (doi:10.1002/humu.22983). (PMID:26931382)

Record type: Article

Abstract

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred 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 (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six 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 twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

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Accepted/In Press date: 17 February 2016
e-pub ahead of print date: 2 March 2016
Published date: July 2016
Keywords: cdg, asparagine-linked glycosylation protein 1, carbohydrate-deficient transferrin, xeno-tetrasaccharide
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 389802
URI: http://eprints.soton.ac.uk/id/eprint/389802
ISSN: 1059-7794
PURE UUID: 7183c15e-eda3-4d8e-bfc2-903d17fa4644

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Date deposited: 15 Mar 2016 15:38
Last modified: 17 Dec 2019 06:54

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Contributors

Author: Bobby G. Ng
Author: Sergey A. Shiryaev
Author: Daisy Rymen
Author: Erik A. Eklund
Author: Kimiyo Raymond
Author: Martin Kircher
Author: Jose E. Abdenur
Author: Fusun Alehan
Author: Alina T. Midro
Author: Michael J. Bamshad
Author: Rita Barone
Author: Gerard T. Berry
Author: Jane E. Brumbaugh
Author: Kati J. Buckingham
Author: Katie Clarkson
Author: F. Sessions Cole
Author: Shawn O'Connor
Author: Gregory M. Cooper
Author: Rudy Van Coster
Author: Laurie A. Demmer
Author: Luisa Diogo
Author: Alexander J. Fay
Author: Can Ficicioglu
Author: Agata Fiumara
Author: William A. Gahl
Author: Rebecca Ganetzky
Author: Himanshu Goel
Author: Lyndsay A. Harshman
Author: Miao He
Author: Jaak Jaeken
Author: Philip M. James
Author: Daniel Katz
Author: Liesbeth Keldermans
Author: Maria Kibaek
Author: Andrew J. Kornberg
Author: Katherine Lachlan
Author: Christina Lam
Author: Joy Yaplito-Lee
Author: Deborah A. Nickerson
Author: Heidi L. Peters
Author: Valerie Race
Author: Luc Régal
Author: Jeffrey S. Rush
Author: S. Lane Rutledge
Author: Jay Shendure
Author: Erika Souche
Author: Susan E. Sparks
Author: Pamela Trapane
Author: Amarilis Sanchez-Valle
Author: Eric Vilain
Author: Arve Vøllo
Author: Charles J. Waechter
Author: Raymond Y. Wang
Author: Lynne A. Wolfe
Author: Derek A. Wong
Author: Tim Wood
Author: Amy C. Yang
Author: Gert Matthijs
Author: Hudson H. Freeze

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