{"doi":"10.3390/biom15091256","title":"Neuromuscular Defects in a Drosophila Model of the Congenital Disorder of Glycosylation SLC35A2-CDG","abstract":"<jats:p>SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG.</jats:p>","journal":"Biomolecules","year":2025,"id":650311,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1695581,"name":"Masaki Kurogochi","orcid":null,"position":1,"is_corresponding":false},{"id":1208334,"name":"Tadashi Kaname","orcid":"0000-0003-0281-9610","position":2,"is_corresponding":false},{"id":1244227,"name":"Jun‐ichi Furukawa","orcid":"0000-0002-7284-2261","position":3,"is_corresponding":false},{"id":495931,"name":"Shoko Nishihara","orcid":"0000-0002-1668-2603","position":4,"is_corresponding":false},{"id":1695580,"name":"Kazuyoshi Itoh","orcid":"0009-0004-5652-1355","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Neuromuscular Defects in a Drosophila Model of the Congenital Disorder of Glycosylation SLC35A2-CDG","abstract":"<jats:p>SLC35A2-CDG is a congenital disorder of glycosylation caused by mutations in the SLC35A2 gene encoding a Golgi-localized UDP-galactose transporter. This transporter plays an essential role in glycan synthesis by transporting UDP-galactose from the cytoplasm into the Golgi lumen. Its dysfunction leads to impaired galactose-containing glycans and various neurological symptoms, although the underlying mechanisms remain largely unknown. We identified a novel SLC35A2-CDG patient carrying a pathogenic variant (c.617_620del, p.(Gln206ArgfsTer45)) who exhibited neurological abnormalities including bilateral ventriculomegaly. To investigate the disease mechanism, we established the first Drosophila model of SLC35A2-CDG. Knockout of Ugalt, the fly ortholog of SLC35A2, resulted in embryonic lethality, indicating its essential role. Knockdown of Ugalt reduced mucin-type O-glycans on muscles and neuromuscular junctions (NMJs), without affecting N-glycans. Ugalt knockdown larvae exhibited mislocalized NMJ boutons accompanied by a deficiency in basement membrane components on muscles. This phenotype resembles that of mutants of dC1GalT1 and dGlcAT-P, both involved in mucin-type O-glycosylation. Genetic interaction between Ugalt and dC1GalT1 was confirmed through double knockdown and double heterozygous analyses. Given that Drosophila NMJs are widely used as a model for mammalian central synapses, our findings suggest that Ugalt regulates NMJ architecture via mucin-type O-glycosylation and provide insights into the molecular basis of neurological abnormalities in SLC35A2-CDG.</jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41008563","pmcid":"PMC12467441","openalex_id":"https://openalex.org/W4413816712","authors":[],"funders":[{"funder_name":"AMED","grant_id":"JP18ek0109288s1602","title":null},{"funder_name":"AMED","grant_id":"JP19ek0109288s0503","title":null},{"funder_name":"AMED","grant_id":"JP25ek0109815s0101","title":null},{"funder_name":"AMED","grant_id":"JP20ek0109301h","title":null},{"funder_name":"AMED","grant_id":"JP24ek0109760s","title":null},{"funder_name":"AMED","grant_id":"JP25ek0109815h0001","title":null},{"funder_name":"AMED","grant_id":"JP25ek0109815s0501","title":null},{"funder_name":"AMED","grant_id":"JP23K14147","title":null},{"funder_name":"AMED","grant_id":"JP23K04954","title":null},{"funder_name":"AMED","grant_id":"2024B-18","title":null}],"total_grants":10,"fwci":1.2498,"citation_percentile":0.80636609,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/2218-273X/15/9/1256/pdf?version=1756481560","host_type":"journal"},{"url":"https://www.mdpi.com/2218-273X/15/9/1256/pdf?version=1756481560","host_type":"publisher"},{"url":"https://www.mdpi.com/2218-273X/15/9/1256/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/biom15091256","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41008563","host_type":"repository"},{"url":"https://doaj.org/article/76fc677091274f91ba89de5bbdf0decc","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12467441","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12467441/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12467441","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12467441?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Lysosomal Storage Disorders Research","Glycosylation and Glycoproteins Research","Glycogen Storage Diseases and Myoclonus"],"mesh_terms":["UDP-Galactose Translocators","Animals","Disease Models, Animal","Drosophila","Drosophila melanogaster","Glycosylation","Humans","Monosaccharide Transport Proteins","Mutation","Neuromuscular Junction","Congenital Disorders of Glycosylation","Drosophila Proteins"],"keywords":["Drosophila (subgenus)","Glycosylation","Neuroscience","Medicine","Physical medicine and rehabilitation","Biology","Genetics","Gene","Drosophila","Basement membrane","Muscle","Neuromuscular junction","T Antigen","Mucin-type O-glycan","Slc35a2-cdg","Ugalt"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"},{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T05:15:09.769442Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}