European structuration for Rett syndrome
1. The european network on Rett Syndrome.
E-Rare is an european initiative to promote research on rare diseases. It is a network of 9 partners from 8 countries
(Belgium, France, Germany, Israel, Italy, Spain, Netherlands, Turkey) wanting to promote trans-national network research on rare diseases.
This program is funded by the European Commission under its 6th framework program since 2006.
The first call was launched in spring 2007. In this context, several laboratories decided to join their forces to propose an european network on Rett Syndrome.
We called our network EuroRETT. After a long internal and external evaluation process, our application was retained for funding among 13 other networks
(among more than 100 applications reviewed).
250 girls affected by the classical form of Rett syndrome are born each year in the member states of the European Union (5 new cases each week).
Among these cases, approximately 90% will have a mutation in the MeCP2 gene and a small proportion will be carrier of a mutation in CDKL5 (mostly
in early onset seizures variant and other atypical Rett syndrome patients). In addition to the mutations identified in typical cases of Rett Syndrome,
an increasing number of mutations or duplications are described in males and females affected by various neurological phenotypes, different from Rett Syndrome.
These phenotype extend from the most severe neonatal encephalopathies to moderate mental retardation.
Despite an homogeneous genetic origin, the phenotype of the patients carrying a mutation in the MeCP2 or CDKL5 gene can be variable and a number of « variant »
phenotypes have been described. However, the relationship between genotype and phenotype remains largely unexplained and clearly needs to be improved.
For this reason, it is important to build large cohorts of patients at the multi-national level. These cohorts will also provide the necessary substrate for
basic research and therapeutic development.Bien que ces cohortes existent dans plusieurs pays, elles sont dispersées et ne sont pas intégrées au niveau européen.
The creation of such an integrated database will constitute the first objective of our network and studying genotype-phenotype correlations
the second objective of the EuroRETT network.
The MECP2 protein is a transcriptional repressor act as transcriptional repressor supposed to act through direct binding to the promoters of target genes
or through chromatin remodelling mechanisms. The CDKL5 protein is able to interact with MECP2 and to modulate its activity. These two proteins could two proteins could
participate in common molecular pathways.However, the mechanisms leading to the severe, progressive and specific neuronal dysfunction when these genes are mutated
are currently unknown.Several laboratories have identified Mecp2 target genes but it is unclear how the abnormal expression of these genes in the context of Mecp2 deficiency
leads to the observed phenotypes. The third objective of the EuroRETT network will be to study the DNA modifications in Rett Syndrome and to study the
targets and interactors of the MECP2 protein.
Several mouse models of Rett syndrome have been generated since year 2000. These models were used to show that the phenotype of the animals was due to Mecp2
dysfunction in the neuronal lineage and, more specifically, in post-mitotic neurons. The neurons of the animal models have abnormal architectural and electrical
properties. The fourth objective of the EuroRETT network will be to study neuronal dysfunction in RS.
Recent key experiments demonstrated that re-expressing Mecp2 in the knock-out mouse displaying overt symptoms was able to reverse disease progression. This
breakthrough discovery shows, for the first time, that a severe neurological disorder can be reversed if appropriate strategies could be used.
This possible reversibility fully justify the development of therapeutic approaches for this disorder, especially pharmacological interventions.
European teams are strongly involved in this research area and this aspect constitutes the fifth objective of the EuroRETT network.
We will pay a special attention to the parent's associations throughout Europe that have supported our application : AFSR in France, ERS in Germany, IRSC in Israel,
AIR and ProRett in Italy, ACSR and AVSR in Spain and also Rett Syndrome Europe. A dedicated website will be installed to present, in lay langage, the work performed in the
network laboratories.
Rett Syndrome is a model disease for several reasons. The causative genes possibly play a role in chromatin remodelling mechanisms which are of major
importance to understand genome regulation, expression and dynamics. Rett syndrome is also a severe phenotype for which there is currently no
efficient treatment but that could be reversible. Also, it is a model of dysfunction of mature neurons. These reasons, combined to the strong commitments of parent
associations to support research, have generated a huge interest for the condition and an important basic and clinical research effort. This type of research could
have a strong impact for other fields of human genetics and neuroscience. This interest is obvious at the european level but the different groups working on these
aspects were not organized to exchange and collaborate efficiently. They are now organized, through this multidisciplinary, trans-national research network called EuroRETT
that is funded for a 3 year period starting in june 2008.
PARTICIPANTS
Team 1
Laurent Villard – Inserm U910 – Marseilles, France (Coordination).
Etienne Joly - IPBS - Toulouse, France.
Team 2
Thierry Bienvenu – Inserm U567 – Paris, France.
Team 3
Vania Broccoli – San Raffaele Institute – Milano, Italy.
Nicoletta Landsberger - University of Insubria - Busto Arsizio, Italy.
Team 4
Cristina Cardoso – Max Delbrück Center – Berlin, Germany.
Maurizio D'Esposito - CNR - Naples, Italy.
Team 5
Manel Esteller – National Cancer Center – Madrid, Spain.
Team 6
Eva Gak – Sheba Medical Center – Tel Hashomer, Israel.
Team 7
Peter Huppke – Georg August Medical School – Göttingen, Germany.
Team 8
Giovanni Laviola – Istituto Superiore di Sanità – Roma, Italy.
Maurizio Giustetto - University of Torino - Torino, Italy.
Tommaso Pizzorusso - CNR - Pisa, Italy.
Team 9
Giovanni Lévi – CNRS 5166 – Paris, France.
Team 10
Silvia Russo – Istituto Auxologico Italiano – Milano, Italy.
Alessandra Renieri - University of Siena - Siena, Italy.
Giorgio Pini - UONPIA - Viareggio, Italy.
2. The European Rett Syndrome Database
Thanks to the EuroRETT network, a european Rett Syndrome database was created. The database is now supervised by Prof. Alessandra Renieri in Siena (Italy). An executive committee was formed to review the proposals requesting the use of deposited informations. The executive committee is composed of clinicians who deposited more than 50 patients.
More informations can be obtained in the website of the database by following that link. In the summer of 2010, 13 countries were willing to contribute (or had already contributed).
3. An annual european Rett Syndrome conference.
Folowing the first meetings organized by ProRett Riccerca or, more recently, by AIR, it was agreed to organize an annual european conference on Rett syndrome. These conferences will be organized each year, excepted the years of the World Congress (next in 2012). They will gather professionals (clinicians and researchers), allied health professionals, caregivers and parents.
The 2010 conference will be held in Edimburgh, under the presidency of Professor Adrian Bird. More informations can be found on the dedicated web site.