{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:12:22Z","timestamp":1793229142987,"version":"4.5.0"},"reference-count":62,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T00:00:00Z","timestamp":1640131200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["GM086524,GM038545,DK99551,U01-CA242096"],"award-info":[{"award-number":["GM086524,GM038545,DK99551,U01-CA242096"]}]},{"name":"National Institute of Health","award":["GM139769"],"award-info":[{"award-number":["GM139769"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,22]]},"abstract":"<jats:p>\n                    The genetic bases for the congenital disorders of glycosylation (CDG) continue to expand, but how glycosylation defects cause patient phenotypes remains largely unknown. Here, we combined developmental phenotyping and biochemical studies in a potentially new zebrafish model (\n                    <jats:italic>\n                      pmm2\n                      <jats:sup>sa10150<\/jats:sup>\n                    <\/jats:italic>\n                    ) of PMM2-CDG to uncover a protease-mediated pathogenic mechanism relevant to craniofacial and motility phenotypes in mutant embryos. Mutant embryos had reduced phosphomannomutase activity and modest decreases in N-glycan occupancy as detected by matrix-assisted laser desorption ionization mass spectrometry imaging. Cellular analyses of cartilage defects in\n                    <jats:italic>\n                      pmm2\n                      <jats:sup>sa10150<\/jats:sup>\n                    <\/jats:italic>\n                    embryos revealed a block in chondrogenesis that was associated with defective proteolytic processing, but seemingly normal N-glycosylation, of the cell adhesion molecule N-cadherin. The activities of the proconvertases and matrix metalloproteinases responsible for N-cadherin maturation were significantly altered in\n                    <jats:italic>\n                      pmm2\n                      <jats:sup>sa10150<\/jats:sup>\n                    <\/jats:italic>\n                    mutant embryos. Importantly, pharmacologic and genetic manipulation of proconvertase activity restored matrix metalloproteinase activity, N-cadherin processing, and cartilage pathology in\n                    <jats:italic>\n                      pmm2\n                      <jats:sup>sa10150<\/jats:sup>\n                    <\/jats:italic>\n                    embryos. Collectively, these studies demonstrate in CDG that targeted alterations in protease activity create a pathogenic cascade that affects the maturation of cell adhesion proteins critical for tissue development.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.153474","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T12:00:41Z","timestamp":1637064041000},"source":"Crossref","is-referenced-by-count":10,"title":["Protease-dependent defects in N-cadherin processing drive PMM2-CDG pathogenesis"],"prefix":"10.1172","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-1449","authenticated-orcid":true,"given":"Elsenoor J.","family":"Klaver","sequence":"first","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Dukes-Rimsky","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brijesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Jie","family":"Xia","sequence":"additional","affiliation":[{"name":"Sanford Children\u2019s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8451-0726","authenticated-orcid":true,"given":"Mark A.","family":"Lehrman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, UT Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peggi","family":"Angel","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Drake","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudson H.","family":"Freeze","sequence":"additional","affiliation":[{"name":"Sanford Children\u2019s Health Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4963","authenticated-orcid":true,"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia."},{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8295-0453","authenticated-orcid":true,"given":"Heather","family":"Flanagan-Steet","sequence":"additional","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia."},{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, 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