Congenital Disorders of Glycosylation: new defects and mechanisms

Congenital Disorders of Glycosylation (CDG) are a group of >150 inherited metabolic disorders. CDG can be caused by the disruption of many aspects of cell biology, from those caused by defects in enzymes catalyzing glycan transfer to those that affect the function of entire organelles, leading to indirect disruption of glycosylation pathways.

This project details the study of two CDG newly identified in our lab. The first of these, DHRSX deficiency, is thought to disrupt the metabolism of dolichol. This is a lipid used as a sugar/glycan carrier for the attachment and formation of N-glycans, as well as having other functions that are poorly understood, such as in the membranes of various organelles. We expect to identify a completely novel step in dolichol metabolism. DHRSX deficiency will also become the first identified truly pseudo-autosomal recessive disorder in human genetics.

The second disorder, caused by mutations in CAMLG, is a defect of the transmembrane domain recognition complex (TRC) pathway, required for the insertion of tail-anchored (TA) proteins into the endoplasmic reticulum membrane. Researching the mechanism by which mutations in CAMLG lead to a CDG will reveal important information about both the TRC pathway and protein trafficking.

In summary, this project will take two diverse novel disorders and use their study to not only describe new aspects of human disease, but also to reveal fundamental and exciting aspects of cell biology.