Congenital disorders of glycosylation (CDGs) are rare, screenable genetic disorders that deplete the synthesis of N-linked glycans. Mutations in PMM2, encoding phosphomannomutase 2 (PMM2, Man-6-P?Man-1-P) cause the most common form, CDG-Ia. Patients have a host of problems including hypotonia, variable psychomotor retardation, seizures, peripheral neuropathy, cardiomyopathy, and protein losing enteropathy. There is no therapy for this disorder. Other patients with CDG-Ib caused by mutations in phosphomannose isomerase (PMI) (Man-6-P Thus Specific Aim 1 will increase the flux of mannose into the glycosylation pathway of Pmm2 deficient cells by knockdown of Pmi or a specific Pmi inhibitor;
Specific Aim 2 will determine to what extent, the specific Pmi inhibitor increases the flux of mannose into glycosylation pathway in normal mice;
and Specific Aim 3 will introduce a hypomorphic Pmi allele into Pmm-deficient mice to rescue embryonic lethality at e18.5 days. This application has high impact because its success would validate a potential small molecule therapy for CDGIa patients. It may also create a flexible mouse model of CDG-Ia based on the addition or withdrawal of mannose from the drinking water. The high risk is that this approach will fail to rescue embryonic lethality or provide sufficient precursors for Pmm2 deficient cells. For CDG-Ia patients without any therapeutic options, the potential impact is worth the risk. PROJECT NARRATIVE: PMM2 deficiency causes congenital disorder of glycosylation (CDG) Type Ia, and no therapy exists. PMI deficiency causes the closely related CDG-Ib where dietary mannose therapy works. Both enzymes compete for the same substrate, mannose-6-P. The investigators predict that CDG-Ia patients will also respond to mannose supplements if the competing PMI activity is reduced. This application aims to validate that hypothesis.

Public Health Relevance

PMM2 deficiency causes Congenital Disorder of Glycosylation (CDG), Type Ia, and no therapy exists. PMI deficiency causes the closely related CDG-Ib where dietary mannose therapy works. Both enzymes compete for the same substrate, Mannose-6-P. We predict that CDG-Ia patients will also respond to mannose supplements if the competing PMI activity is reduced. This proposal aims to validate that hypothesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD062914-01
Application #
7778064
Study Section
Special Emphasis Panel (ZHD1-MRG-C (07))
Program Officer
Oster-Granite, Mary Lou
Project Start
2010-04-15
Project End
2012-03-31
Budget Start
2010-04-15
Budget End
2011-03-31
Support Year
1
Fiscal Year
2010
Total Cost
$266,562
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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