{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:27:51Z","timestamp":1791275271976,"version":"4.1.0"},"reference-count":44,"publisher":"American Society for Cell Biology (ASCB)","issue":"21","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:p> Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P). Patients have wide-spectrum clinical abnormalities associated with impaired protein N-glycosylation. Although it has been widely proposed that Pmm2 deficiency depletes M1P, a precursor of GDP-mannose, and consequently suppresses lipid-linked oligosaccharide (LLO) levels needed for N-glycosylation, these deficiencies have not been demonstrated in patients or any animal model. Here we report a morpholino-based PMM2-CDG model in zebrafish. Morphant embryos had developmental abnormalities consistent with PMM2-CDG patients, including craniofacial defects and impaired motility associated with altered motor neurogenesis within the spinal cord. Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants. Although M1P and GDP-mannose were below reliable detection\/quantification limits, Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro. In pmm2 morphants, the free glycan by-products of LLO cleavage increased nearly twofold. Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the pmm2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated pmm2-dependent LLO cleavage. In summary, we report the first zebrafish model of PMM2-CDG and uncover novel cellular insights not possible with other systems, including an M6P accumulation mechanism for underglycosylation. <\/jats:p>","DOI":"10.1091\/mbc.e12-05-0411","type":"journal-article","created":{"date-parts":[[2012,9,6]],"date-time":"2012-09-06T20:26:04Z","timestamp":1346963164000},"page":"4175-4187","source":"Crossref","is-referenced-by-count":57,"title":["A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency"],"prefix":"10.1091","volume":"23","author":[{"given":"Abigail","family":"Cline","sequence":"first","affiliation":[{"name":"Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningguo","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 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