Glycobiology is considered as an emerging field of biology and the importance of complex carbohydrates in health and disease is increasingly recognized. In the last decade, a new group of diseases related to defects of glycosylation and called Congenital Disorders of Glycosylation has been identified. According to the cellular localization of the deficiency, CDG can be divided into two groups, CDG-I and CDG-II. Group I disorders relate to defects in the synthesis of the N-glycans in the endoplasmic reticulum. This project relates to Group II disorders, which arise from the defects in the processing of the glycans, mainly in the Golgi apparatus. Whereas all known CDG cases so far have defects in genes encoding proteins directly involved in the glycosylation process, our previous works highlighted that more cases may be linked to a defect of intracellular trafficking within the Golgi apparatus. This greatly expands the number of potential candidate genes and the proposed research aims at identifying new unsolved CDG-II patients with a trafficking deficiency in which localization and/or trafficking of Golgi associated glycosyltransferases appears disturbed. The first part of the project will be devoted to the screening of unsolved CDG-II patients for trafficking deficiencies and the second part will concern the identification of a new gene causing a new type of CDG with significant neuromuscular involvement. Indeed, we recently identified two patients in two different families with CDG and a very specific phenotype that includes myopathy, encephalopathy and epiphyseal hypoplasia. However and surprisingly, it appears that the patient cells also display a trafficking deficiency. We will aim to demonstrate the pathogenic nature of the unusual, homozygous mutation that we have identified in this gene, and prove its involvement in both glycosylation and trafficking deficiencies. Using the zebrafish model, we will next try to unravel its role in the development.
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