Defining causes of Congenital Disorders of Gylcosylation

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): The causes of CDG in many patients are undiscovered. The aim is to develop a novel method to identify CDG mutations that are not solved by traditional methods. There are three specific aims: 1. Establish which CDG cell lines are poorly transduced by Adeno-associated virus (AAV) AAV4 and 5. 2. Complement those CDG cells with a cDNA library, identify complemented cells by AAV, and sequence the complementing cDNA. 3. Identify mutations in CDG cells and correct abnormal glycosylation with normal cDNA. Aim 1 is to determine which CDG cells are suitable for complemetation. Only those cells that are not efficiently transduced by viral vectors AAV4 and AAV5 can be used by this method. Aim 2&3 identify the causes of CDG. Four steps are needed. First, CDG cells are transduced by a human liver retroviral cDNA library. Second, the rescued cells are identified by AAV transduction. Third, complemented cDNAs are identified by RT-PCR and mutations in patients are identified by sequencing. The last step is correcting abnormal glycosylation by complementing patient's cells with the specific wild type genes. The long-term goals are to discover new types of CDG and understand the relationship among mutations, glycosylation and pathology.