{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ALG13 is a conserved protein that functions as the catalytic component of a unique hetero‐oligomeric UDP–N‐acetylglucosamine transferase required for the early steps of N–linked glycosylation. In both yeast and human cells, ALG13 catalyzes the addition of a GlcNAc moiety to the growing dolichol–linked oligosaccharide precursor on the cytosolic face of the endoplasmic reticulum. Because ALG13 lacks intrinsic membrane–spanning domains, its recruitment to the ER relies on its physical association with the membrane protein ALG14, which serves as an essential anchor to position the catalytic ALG13 in proximity to its lipid substrate."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " Structural and biochemical studies have revealed that ALG13 possesses a unique catalytic domain with distinct glycosyl donor–binding properties and is tightly regulated at the level of protein stability—its unassembled form is rapidly degraded, ensuring proper quality control and accurate complex assembly."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Pathogenic variants in ALG13 have been implicated in a spectrum of neurological disorders. Clinical studies have linked mutations—including recurrent de novo missense changes such as p.(Asn107Ser)—to early–onset epileptic encephalopathy, intellectual disability, and congenital disorders of glycosylation, often with normal conventional glycosylation profiles despite altered enzyme function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": " Experimental animal models further demonstrate that ALG13 deficiency exacerbates seizure susceptibility and may lead to alterations in neuronal signaling pathways, such as mTOR, thereby contributing to the severe neurodevelopmental phenotypes observed in affected individuals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these findings establish ALG13 as a critical glycosyltransferase whose proper function is indispensable for the synthesis of glycoproteins and normal neurological development. Disruption of its activity—whether by genetic mutations that alter its catalytic efficiency or by impairing its recruitment to the ER—results in aberrant glycosylation and is associated with a range of neurodevelopmental and epileptic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Unknown Authors "}, {"type": "b", "children": [{"type": "t", "text": "De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2016.06.003"}], "href": "https://doi.org/10.1016/j.ajhg.2016.06.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27476654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27476654"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Judith Cossins, Katsiaryna Belaya, Debbie Hicks, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Congenital myasthenic syndromes due to mutations in ALG2 and ALG14."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Brain (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/brain/awt010"}], "href": "https://doi.org/10.1093/brain/awt010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23404334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23404334"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Xiao-Dong Gao, Hiroyuki Tachikawa, Takashi Sato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alg14 recruits Alg13 to the cytoplasmic face of the endoplasmic reticulum to form a novel bipartite UDP-N-acetylglucosamine transferase required for the second step of N-linked glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M507569200"}], "href": "https://doi.org/10.1074/jbc.M507569200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16100110"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16100110"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nicole Averbeck, Sabine Keppler-Ross, Neta Dean "}, {"type": "b", "children": [{"type": "t", "text": "Membrane topology of the Alg14 endoplasmic reticulum UDP-GlcNAc transferase subunit."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704410200"}], "href": "https://doi.org/10.1074/jbc.M704410200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17686769"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17686769"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Nicole Averbeck, Xiao-Dong Gao, Shin-Ichiro Nishimura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alg13p, the catalytic subunit of the endoplasmic reticulum UDP-GlcNAc glycosyltransferase, is a target for proteasomal degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e07-10-1077"}], "href": "https://doi.org/10.1091/mbc.e07-10-1077"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18337470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18337470"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xu Wang, Thomas Weldeghiorghis, Guofeng Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Solution structure of Alg13: the sugar donor subunit of a yeast N-acetylglucosamine transferase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Structure (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.str.2008.03.010"}], "href": "https://doi.org/10.1016/j.str.2008.03.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18547528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18547528"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Nesrine Bissar-Tadmouri, Whithey L Donahue, Lihadh Al-Gazali, et al. "}, {"type": "b", "children": [{"type": "t", "text": "X chromosome exome sequencing reveals a novel ALG13 mutation in a nonsyndromic intellectual disability family with multiple affected male siblings."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.36233"}], "href": "https://doi.org/10.1002/ajmg.a.36233"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24501762"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24501762"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Peng Gao, Feng Wang, Junming Huo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALG13 Deficiency Associated with Increased Seizure Susceptibility and Severity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuroscience (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuroscience.2019.03.009"}], "href": "https://doi.org/10.1016/j.neuroscience.2019.03.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30872163"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30872163"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Sana Hamici, Fatma Bastaki, Mohamed Khalifa "}, {"type": "b", "children": [{"type": "t", "text": "Exome sequence identified a c.320A > G ALG13 variant in a female with infantile epileptic encephalopathy with normal glycosylation and random X inactivation: Review of the literature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2017.07.014"}], "href": "https://doi.org/10.1016/j.ejmg.2017.07.014"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28778787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28778787"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Alexandre N Datta, Nadia Bahi-Buisson, Thierry Bienvenu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epilepsia (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/epi.16761"}], "href": "https://doi.org/10.1111/epi.16761"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33410528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33410528"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Hind Alsharhan, Miao He, Andrew C Edmondson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ALG13 X-linked intellectual disability: New variants, glycosylation analysis, and expanded phenotypes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Inherit Metab Dis (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jimd.12378"}], "href": "https://doi.org/10.1002/jimd.12378"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33734437"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33734437"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Andrea Accogli, Silvia Radenkovic, Wasantha Ranatunga, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Could distal variants in ALG13 lead to atypical clinical presentation?"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2022.104473"}], "href": "https://doi.org/10.1016/j.ejmg.2022.104473"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35240324"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35240324"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Karolina Mitusińska, Artur Góra, Anna Bogdańska, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural Analysis of the Effect of Asn107Ser Mutation on Alg13 Activity and Alg13-Alg14 Complex Formation and Expanding the Phenotypic Variability of ALG13-CDG."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biomolecules (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/biom12030398"}], "href": "https://doi.org/10.3390/biom12030398"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35327592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35327592"}]}]}]}