Molecular Studies of Brain Malformations

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DESCRIPTION (provided by applicant): 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.