A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation

Autor: Richard Steet, Sabrina Rosa, Ningguo Gao, Jaime Chu, Mark A. Lehrman, Vandana Sharma, Kirsten C. Sadler, Christopher Monson, Alexander Mir, Hudson H. Freeze
Jazyk: angličtina
Rok vydání: 2013
Předmět:
medicine.medical_specialty
Glycosylation
Morpholino
Neuroscience (miscellaneous)
Medicine (miscellaneous)
Mannose
lcsh:Medicine
Biology
medicine.disease_cause
General Biochemistry
Genetics and Molecular Biology
Morpholinos
03 medical and health sciences
chemistry.chemical_compound
Liver disease
Mice
0302 clinical medicine
Congenital Disorders of Glycosylation
Immunology and Microbiology (miscellaneous)
Internal medicine
medicine
lcsh:Pathology
Animals
Humans
Zebrafish
030304 developmental biology
0303 health sciences
Mutation
Mannose-6-Phosphate Isomerase
Base Sequence
lcsh:R
biology.organism_classification
medicine.disease
Phenotype
3. Good health
Disease Models
Animal
Endocrinology
Secretory protein
chemistry
Gene Knockdown Techniques
Immunology
Dietary Supplements
030217 neurology & neurosurgery
Research Article
lcsh:RB1-214
Zdroj: Disease Models & Mechanisms, Vol 6, Iss 1, Pp 95-105 (2013)
Disease Models & Mechanisms
ISSN: 1754-8411
1754-8403
Popis: Summary 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.
Databáze: OpenAIRE
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