{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T16:13:58Z","timestamp":1791044038806,"version":"4.1.0"},"reference-count":42,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":3425,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Individuals with congenital disorders of glycosylation (CDG) have recessive mutations in genes required for protein N-glycosylation, resulting in multi-systemic disease. Despite the well-characterized biochemical consequences in these individuals, the underlying cellular defects that contribute to CDG are not well understood. Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme. Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis. MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress. Because Mpi deletion in mice causes early embryonic lethality and thus is difficult to study, we used zebrafish to establish a model of MPI-CDG. We used a morpholino to block mpi mRNA translation and established a concentration that consistently yielded 13% residual Mpi enzyme activity at 4 days post-fertilization (dpf), which is within the range of MPI activity detected in fibroblasts from MPI-CDG patients. Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants. These deficiencies resulted in 50% embryonic lethality by 4 dpf. Multi-systemic abnormalities, including small eyes, dysmorphic jaws, pericardial edema, a small liver and curled tails, occurred in 82% of the surviving larvae. Importantly, these phenotypes could be rescued with mannose supplementation. Thus, parallel processes in fish and humans contribute to the phenotypes caused by Mpi depletion. Interestingly, mannose was only effective if provided prior to 24 hpf. These data provide insight into treatment efficacy and the broader molecular and developmental abnormalities that contribute to disorders associated with defective protein glycosylation.<\/jats:p>","DOI":"10.1242\/dmm.010116","type":"journal-article","created":{"date-parts":[[2012,8,17]],"date-time":"2012-08-17T03:27:25Z","timestamp":1345174045000},"source":"Crossref","is-referenced-by-count":21,"title":["A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation"],"prefix":"10.1242","author":[{"given":"Jaime","family":"Chu","sequence":"first","affiliation":[{"name":"Mount Sinai School of Medicine, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Mir","sequence":"additional","affiliation":[{"name":"Mount Sinai School of Medicine, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningguo","family":"Gao","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center, Dallas, TX, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Rosa","sequence":"additional","affiliation":[{"name":"Mount Sinai School of Medicine, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Monson","sequence":"additional","affiliation":[{"name":"Mount Sinai School of Medicine, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Sharma","sequence":"additional","affiliation":[{"name":"Sanford-Burnham Medical Research Center, La Jolla, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"University of Georgia, Athens, GA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hudson H.","family":"Freeze","sequence":"additional","affiliation":[{"name":"Sanford-Burnham Medical Research Center, La Jolla, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Lehrman","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center, Dallas, TX, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten C.","family":"Sadler","sequence":"additional","affiliation":[{"name":"Mount Sinai School of Medicine, NY, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2021042423051780800_b1-0060095","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/S0022-3476(99)70103-4","article-title":"Severe hypoglycemia as a presenting symptom of carbohydrate-deficient glycoprotein syndrome","volume":"135","author":"Babovic-Vuksanovic","year":"1999","journal-title":"J. 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Nutr."},{"key":"2021042423051780800_b7-0060095","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1006\/bbrc.1998.8385","article-title":"A novel disorder of N-glycosylation due to phosphomannose isomerase deficiency","volume":"245","author":"de Koning","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021042423051780800_b8-0060095","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.bbadis.2008.11.012","article-title":"The clinical spectrum of phosphomannose isomerase deficiency, with an evaluation of mannose treatment for CDG-Ib","volume":"1792","author":"de Lonlay","year":"2009","journal-title":"Biochim. Biophys. 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