{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T23:24:53Z","timestamp":1788305093087,"version":"build-2803163510"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T00:00:00Z","timestamp":1694044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>GM3 Synthase Deficiency (GM3SD) is a neurodevelopmental disorder resulting from pathogenic variants in the ST3GAL5 gene, which encodes GM3 synthase, a glycosphingolipid (GSL)-specific sialyltransferase. This enzyme adds a sialic acid to the terminal galactose of lactosylceramide (LacCer) to produce the monosialylated ganglioside GM3. In turn, GM3 is extended by other glycosyltransferases to generate nearly all the complex gangliosides enriched in neural tissue. Pathogenic mechanisms underlying the neural phenotypes associated with GM3SD are unknown. To explore how loss of GM3 impacts neural-specific glycolipid glycosylation and cell signaling, GM3SD patient fibroblasts bearing one of two different ST3GAL5 variants were reprogrammed to induced pluripotent stem cells (iPSCs) and then differentiated to neural crest cells (NCCs). GM3 and GM3-derived gangliosides were undetectable in cells carrying either variant, while LacCer precursor levels were elevated compared to wildtype (WT). NCCs of both variants synthesized elevated levels of neutral lacto- and globo-series, as well as minor alternatively sialylated GSLs compared to WT. Ceramide profiles were also shifted in GM3SD variant cells. Altered GSL profiles in GM3SD cells were accompanied by dynamic changes in the cell surface proteome, protein O-GlcNAcylation, and receptor tyrosine kinase abundance. GM3SD cells also exhibited increased apoptosis and sensitivity to erlotinib-induced inhibition of epidermal growth factor receptor signaling. Pharmacologic inhibition of O-GlcNAcase rescued baseline and erlotinib-induced apoptosis. Collectively, these findings indicate aberrant cell signaling during differentiation of GM3SD iPSCs and also underscore the challenge of distinguishing between variant effect and genetic background effect on specific phenotypic consequences.<\/jats:p>","DOI":"10.1093\/hmg\/ddad146","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T17:04:50Z","timestamp":1694019890000},"page":"3323-3341","source":"Crossref","is-referenced-by-count":12,"title":["Neural-specific alterations in glycosphingolipid biosynthesis and cell signaling associated with two human ganglioside GM3 synthase deficiency variants"],"prefix":"10.1093","volume":"32","author":[{"given":"Michelle","family":"Dookwah","sequence":"first","affiliation":[{"name":"University of Georgia Complex Carbohydrate Research Center, , 315 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon K","family":"Wagner","sequence":"additional","affiliation":[{"name":"University of Georgia Complex Carbohydrate Research Center, , 315 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayumi","family":"Ishihara","sequence":"additional","affiliation":[{"name":"University of Georgia Complex Carbohydrate Research Center, , 315 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok-Ho","family":"Yu","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , 106 Gregor Mendel Circle, Greenwood, SC 29646 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Ulrichs","sequence":"additional","affiliation":[{"name":"University of Georgia Center for Molecular Medicine, , 325 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Kulik","sequence":"additional","affiliation":[{"name":"University of Georgia Center for Molecular Medicine, , 325 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Zeltner","sequence":"additional","affiliation":[{"name":"University of Georgia Center for Molecular Medicine, , 325 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Dalton","sequence":"additional","affiliation":[{"name":"University of Georgia Center for Molecular Medicine, , 325 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A","family":"Strauss","sequence":"additional","affiliation":[{"name":"Clinic for Special Children , 535 Bunker Hill Road, Strasburg, PA 17579 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Aoki","sequence":"additional","affiliation":[{"name":"University of Georgia Complex Carbohydrate Research Center, , 315 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4963","authenticated-orcid":false,"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"Greenwood Genetic Center , 106 Gregor Mendel Circle, Greenwood, SC 29646 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8704-9143","authenticated-orcid":false,"given":"Michael","family":"Tiemeyer","sequence":"additional","affiliation":[{"name":"University of Georgia Complex Carbohydrate Research Center, , 315 Riverbend Road, Athens, GA 30602 , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,9,7]]},"reference":[{"key":"2023120422225847300_ref1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ymgme.2019.01.013","article-title":"Recessive GM3 synthase deficiency: natural history, biochemistry, and therapeutic frontier","volume":"126","author":"Bowser","year":"2019","journal-title":"Mol Genet Metab"},{"key":"2023120422225847300_ref2","first-page":"6","volume-title":"Proc. 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