[SMC] ALG14 Variants Contribute to a Congenital Disorder of Glycosylation Characterized by Congenital Myasthenia and Epi

[RSS-Bot]

HGG Adv. 2026 Jul 8:100650. doi: 10.1016/j.xhgg.2026.100650. Online ahead of print.

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 glycosylation of a wide array of proteins. Biallelic 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 the 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. These findings may guide evaluation of future individuals with suspected ALG14-CDG and future targeted therapeutics such as those being used in other CDG.

PMID:42421312 | DOI:10.1016/j.xhgg.2026.100650


Source: https://pubmed.ncbi.nlm.nih.gov/4242131 ... 9&v=2.20.0