ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epilepsy
Abstract
Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to the glycosylation of a wide array of proteins. Bi-allelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid-linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families, we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants, as well as missense variants from the individuals reported in this study. Investigations of Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a bona fide CDG. In the future, these findings may guide the evaluation of individuals with suspected ALG14-CDG and targeted therapeutics such as those being used in other CDGs. Keywords
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BibTeX
@article{marquez2026alg14,
title = {{ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epilepsy}},
author = {Jonathan Marquez and Flavien Rouxel and Fatima It and Victor Couturier and Laurence Duplomb and Valentin Bourgeois and Anne-Sophie Briffaut and Ange-Line Bruel and Martin Chevarin and Benjamin Ganne and Bobby Ng and Stephen Viviano and Mara P.N. Hektor and Rafia Pasha and Vincent Gatinois and Camille Larrieu-Arguille and Jean-Michel Faure and Olivier Prodhomme and Maxime Colmard and François Rivier and Okubo Yukimune and Charlotte Poe and Isabelle Rouvet and Antonio Vitobello and Christel Thauvin and Gerardo Rodriguez-Gomez and Leandra Tolusso and Yu Katata and Atsuo Kikuchi and Trevor Hoffman and Hans Andersson and Engin Deniz and Miao He and Constance Wells and Anne-Sophie Denommé-Pichon and Andrew Edmondson and Hudson Freeze and Christina Lam},
journal = {Human Genetics and Genomics Advances},
year = {2026},
month = nov,
doi = {10.1016/j.xhgg.2026.100650},
url = {https://hal.science/hal-05688968v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epilepsy
AU - Jonathan Marquez
AU - Flavien Rouxel
AU - Fatima It
AU - Victor Couturier
AU - Laurence Duplomb
AU - Valentin Bourgeois
AU - Anne-Sophie Briffaut
AU - Ange-Line Bruel
AU - Martin Chevarin
AU - Benjamin Ganne
AU - Bobby Ng
AU - Stephen Viviano
AU - Mara P.N. Hektor
AU - Rafia Pasha
AU - Vincent Gatinois
AU - Camille Larrieu-Arguille
AU - Jean-Michel Faure
AU - Olivier Prodhomme
AU - Maxime Colmard
AU - François Rivier
AU - Okubo Yukimune
AU - Charlotte Poe
AU - Isabelle Rouvet
AU - Antonio Vitobello
AU - Christel Thauvin
AU - Gerardo Rodriguez-Gomez
AU - Leandra Tolusso
AU - Yu Katata
AU - Atsuo Kikuchi
AU - Trevor Hoffman
AU - Hans Andersson
AU - Engin Deniz
AU - Miao He
AU - Constance Wells
AU - Anne-Sophie Denommé-Pichon
AU - Andrew Edmondson
AU - Hudson Freeze
AU - Christina Lam
PY - 2026
DA - 2026/11/03
JO - Human Genetics and Genomics Advances
DO - 10.1016/j.xhgg.2026.100650
UR - https://hal.science/hal-05688968v1
AB - Asparagine-linked glycosylation 14 (ALG14) is a UDP-GlcNAc transferase that catalyzes the second sugar addition in the synthesis of the dolichol-linked oligosaccharide precursor in N-linked glycosylation, ultimately contributing to the glycosylation of a wide array of proteins. Bi-allelic pathogenic variants in ALG14 have been suggested to lead to a congenital disorder of glycosylation (CDG) due to incomplete lipid-linked oligosaccharide synthesis and ultimately hypoglycosylation of N-linked glycoproteins. In a cohort of nine previously unreported individuals with bi-allelic variants in ALG14 from eight unrelated families, we demonstrate evidence of a CDG that manifests as a congenital myasthenic syndrome, epilepsy, joint contractures, and dysmorphic features. Using a Xenopus knockdown model of disease, we explored the ramifications of alg14 depletion on early neurodevelopment and used this model as a platform to test the function of previously identified ALG14 missense variants, as well as missense variants from the individuals reported in this study. Investigations of Xenopus model tissue and tissue from an affected individual elucidated a mechanism by which dysfunctional glycosylation may lead to neurological disease and establish this as a bona fide CDG. In the future, these findings may guide the evaluation of individuals with suspected ALG14-CDG and targeted therapeutics such as those being used in other CDGs. Keywords
SN - 2666-2477
ER -