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A systematic approach towards the understanding, diagnosis and treatment of cdgs, a novel group of inborn metabolic disorders caused by defects of glycosylation

Objective

EUROGLYCAN will focus on a novel group of rare metabolic diseases caused by defects in protein glycosylation. The defects result in mental retardation, severe disease and physical handicap. Our major aims are to :
1) develop effective tools and promote early diagnosis;
2) collate patient information, useful for the identification and classification of novel types;
3) raise awareness, because the disorders are largely unrecognised;
4) establish a patient group large enough for systematic investigations and clinical trials.
To fulfil these aims,
1) a database will be created, maintained by the reference centre and accessible through Internet;
2) the material will be reviewed and a depository of cell lines will be generated;
3) diagnostic services will be made widely available;
4) interesting cases will be selected for research;
5) (mouse)models will be developed;
6) collaborations will be sought with companies for the development of therapies.
The project aimed at streamlining the diagnostic approach towards CDG. The number of diagnosed patients has increased thanks to the fact that the network has been offering free, expert diagnostic work-up of the clinical cases. At the end of the project, more than 400 cases have been compiled. EUROGLYCAN has certainly achieved to bring together the leading European groups with an interest and expertise in CDG and related syndromes. The close collaboration of several clinical and fundamental research groups has been key to the success. The activities were structured around a database, maintained at the reference centre. The main and the satellite clinical centres were involved in the recruitment of samples. The most interesting cases were forwarded to the research laboratories from the network.

In addition, EUROGLYCAN has created new national referral centres for CDG. At the same time, the network continually supported fundamental research and the development of yeast and mouse models for the disease. From a basic research standpoint, there was a remarkable progress in CDG-I, with the identification of 8 novel defects in the endoplasmatic reticulum (ER) by members of the network (CDG-Id, Ie, If, Ig, Ih, Ii, Ik and - still unpublished - Il). In spite of a strong focus on Golgi defects (CDG-II), where, among other techniques, N-glycan analysis was used to identify defects, there were only a few breakthroughs in this area, with the identification of CDG-IIc and CDG-IId. Still, the technologies have evolved, and we will witness, in the next few years, the same success in the elucidation of novel defects in the Golgi as previously in the ER.

In the course of the project, different tools for the analysis of glycans and the identification of glycosylation defects, and different models for the study of the pathogenesis of the diseases have been developed by members of the EUROGLYCAN network. Platforms for mutation analysis for the streamlining of molecular diagnostics and mass spectrometry (MALDI-TOF), and more accessible techniques like DNA-FACE, have been introduced and are ready to be spread across diagnostic groups in the different parts of Europe.
Models in yeast have been established. Thus, new tools for the study of glycosylation defects are available. Unfortunately, the Pmm2 knock-out mice show a very early embryonic lethality, which makes it is impossible to study it as a model for CDG-Ia. This problem will be circumvented by the generation of mice that carry 2 'human' mutations in the endogenous Pmm2 gene. The work for other mouse knock-outs is still in progress. In the mean time, the Pmm1 and Pmm2 expression in normal mice has been studied by immunohistochemistry. EUROGLYCAN has also focussed on training and education. For professionals in the field, EUROGLYCAN has organised the first international meetings, and the first course, specifically dedicated to CDG. In parallel, efforts have been made to raising awareness on the disease among paediatricians and other medical specialists. Also, information has been made available on the EUROGLYCAN website.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
Address
49,Herestraat 49
3000 Louvain / Leuven
Belgium

Participants (7)

CHRISTIAN DE DUVE INSTITUTE OF CELLULAR PATHOLOGY
Belgium
Address
Avenue Hippocrate 75, Icp 75.50
Bruxelles
FACULTY OF MEDICINE/UNIVERSITY HOSPITAL GOETTINGEN
Germany
Address
Heinrich Dueker Weg, 12
37073 Goettingen
HOSPITAL CLINIC BARCELONA
Spain
Address
170,Calle Villaroel 170
08036 Barcelona
STICHTING KATHOLIEKE UNIVERSITEIT
Netherlands
Address

6500 GL Nijmegen
SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZUERICH
Switzerland
Address
101,Raemistrasse 101, Eth Zentrum
8092 Zurich
UNIVERSITY COLLEGE LONDON
United Kingdom
Address
30,Guilford Street 30
WC1N 1EH London
UNIVERSITY OF ZURICH
Switzerland
Address
71,Raemistrasse 71
CH-8091 Zurich