Congenital muscular dystrophies (CMD) with brain malformations such as muscle-eye- brain disease (MEB) are genetic diseases characterized by cortical dysplasia, ocular abnormalities, and muscular dystrophy. The protein products of the offending genes encode glycosyltransferases involved in glycosylation of proteins. Of particular importance are glycans O-linked to proteins by the sugar mannose. O-mannosyl glycans are formed by the addition of mannose to Ser/Thr residues by POMT1 and POMT2, followed by the 21, 2 addition of N-acetylglucosamine to the mannose by POMGnT1. Genetic deficiencies of these lead to 1-dystroglycan hypoglycosylation and produce CMD phenotypes. Mutations in the gene Large cause similar phenotypes. While the biochemical functions of Large are unknown, overexpression of Large can hyperglycosylate 1-dystroglycan in cells isolated from other CMD patients, suggesting that Large may be developed as a therapeutic agent for gene therapy of CMD. The hypothesis is that Large synthesizes a glycan(s) distinct from O-mannosyl glycans.
The specific aims are to investigate: 1. The roles of Large in dystroglycan glycosylation and function. 2. The feasibility of using Large in gene therapy in vivo. By characterizing the carbohydrate profiles of 1-dystroglycan under Large loss- and gain-of-functions, the proposed research will provide new and important insights into the molecular functions of Large. In addition, it will test the feasibility of using Large as a gene therapeutic agent for the POMGnT1 deficiency in vivo.

Public Health Relevance

Congenital muscular dystrophies with brain malformations are caused by genetic mutations to glycosyltransferases involved in protein glycosylation. This project studies the molecular and cellular mechanisms of brain malformations caused by defective glycosylation and the feasibility of using an enzyme as a therapeutic agent in congenital muscular dystrophies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
9R01NS066582-05A1
Application #
7580664
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Porter, John D
Project Start
2003-04-01
Project End
2012-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
5
Fiscal Year
2009
Total Cost
$206,063
Indirect Cost
Name
Upstate Medical University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
058889106
City
Syracuse
State
NY
Country
United States
Zip Code
13210
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