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Vesicular Golgi trafficking deficiencies in unsolved CDG type II patients

Final Report Summary - VTG-CDG (Vesicular Golgi trafficking deficiencies in unsolved CDG type II patients)

Thanks to this reintegration grant, our group was able to identify and characterise molecular defects responsible for a family of rare autosomal recessive disorders caused by defects in the biosynthesis of protein-linked glycans and named congenital disorders of glycosylation (CDG). In order to identify new defects, our strategy was based either on structural characterisation of lipid-linked oligosaccharides (LLO) after metabolic labelling and/or autozygosity mapping in consanguineous families. This project has benefited from a large collection of known and unsolved CDG patients available in Leuven (Pr Gert Matthijs). Collaborative efforts are still required to achieve the ambitious task of solving these patients and this is why our group is closely collaborating with the group of Prof G. Matthijs but also with other European groups with interests in CDG.

During the grant period; this strategy proved to be extremely efficient as it allowed us to identify many novel genes responsible for CDG. We indeed found four new CDG-II patients with a COG (conserved oligomeric golgi complex) deficiency, respectively in Cog1 (Foulquier et al., 2006), Cog8 (Foulquier et al., 2007; Zeevaert, Foulquier et al., 2009), Cog4 (Reynders, Foulquier et al., 2009), and an additional patient with a Cog7 deficiency (Zeevaert, Foulquier et al., 2009). The research on CDG-I has also been particularly successful and allowed us to pinpoint the genetic defects in eight patients. We identified five patients with a RFT1 deficiency (Vleugels et al., 2009), one patient with an ALG9 deficiency ( Vleugels et al., 2009) and two patients with mutations in two OST subunits genes N33/TUSC3 and IAP, respectively (Molinari, Foulquier et al., 2008).

The proposed project was situated at the interface between research in pathology and fundamental research in glycobiology. This project was combining knowledge from the genetics and glycobiology, to further characterise the molecular and biochemical basis of these inborn errors of glycosylation. From a fundamental research point of view, the study of these CDG patients with altered glycosylation led us to major breakthroughs towards the elucidation of the basic defects and provided us new insights into the basic endoplasmic reticulum (ER) and golgi glycosylation mechanisms. "