Joint Transnational Call 2007 (JTC2007)


Rett syndrome (RTT, MIM 312750) is a severe neurological disorder, mostly sporadic, and primarily affecting girls, with an incidence of about 1/10,000 female births (300 girls affected by Rett syndrome born each year in the European Union). The patients develop normally during the first 6 to 18 months of life and then progressively show symptoms including loss of motor and cognitive skills, stereotypic hand movements, seizures and autonomic dysfunction. More than 95% of the RTT patients carry a mutation in the methyl-CpG binding protein 2 (MECP2) gene. A proportion of Rett syndrome clinical variants are due to the presence of mutations in the CDKL5 or FOXG1 genes. In addition to the mutations in female cases of classical Rett syndrome, an ever increasing number of mutations and duplications of MECP2 are described in male and female patients with different neurodevelopmental phenotypes ranging from severe neonatal encephalopathies to mild mental retardation. Rett syndrome is a model for autism-spectrum disorders and the causative genes play a role in mechanisms that 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 based on the results obtained in animal models. These reasons, combined to the strong commitments of parent associations to support research, have generated a huge interest for the condition. Given the complex nature of this disease, we were convinced that a multidisciplinary, trans-national research network was needed. In 2008, the ERARE call was an opportunity to organize, to exchange and to collaborate more efficiently at the european level. 

Creation of the world’s largest Rett syndrome database
The relationship between genotype and phenotype remains largely unexplained and clearly needs to be improved in RTT. It was important to build large cohorts of patients at the international level. These cohorts will provide the necessary substrate for basic research and therapeutic development. If RTT cohorts were existing in different countries, they were scattered and not integrated at the european level. A network of databases was created through EuroRETT. Since december 2009, the European Rett Syndrome Database Network is available through the internet at As of march 2012, the database network contains clinical and molecular information for 1834 patients originating from 10 european countries (and plans are underway to include patients from 7 additional countries). Data mining for registered users is available since december 2010. This database will be particularly useful for clinical and basic research as well as for patient identification in the upcoming clinical trials. The database was financially supported by EuroRETT and by several european RTT patient associations (AIR in Italy, AFSR in France and ACSR in Spain).

Identification of a new cause of RTT
Mutations in the FOXG1 gene have been identified in RTT cases negative for mutations in the MECP2 and CDKL5 genes. Before it was shown to be responsible for a variant form of Rett syndrome, defects of the FOXG1 gene had been described in patients with severe intellectual disability, cerebral malformations and microcephaly. The involvement of FOXG1 in a variant form of Rett syndrome was published in 2008 in children affected by the congenital variant of Rett syndrome. This discovery was made possible by the previous finding of a chromosomal rearrangement involving the FOXG1 gene in a patient with clinical signs overlapping that of Rett syndrome.

Major contributions to the scientific litterature to understand neuronal dysfunction in RTT
A large amount of work has been performed by EuroRETT laboratories to understand neuronal dysfunction caused by MECP2, CDKL5 or FOXG1 dysfunction. Alteration of the stability of microtubules and of neuronal trafficking were found together with defects of chromatin architecture, neuronal excitability and morphology or abnormal micro-RNA regulations in Mecp2-deficient cells or tissues. Several new interacting partners for MECP2 have been identified and are being studied to determine how they impact disease progression. Two EuroRETT laboratories performed in depth studies of CDKL5 function while others developed new mouse models.

Development of therapeutic strategies in pre-clinical models
Mouse models of RTT or patient cell lines have been treated with pharmacological agents to develop new therapeutic strategies. Varying degrees of efficiency were reported by EuroRETT laboratories for L-DOPA, desipramine, cysteamine, gentamycin, hygromycin D, valproic acid, choline or new readthrough compounds.

  • Villard, Laurent (Coordinator)
    INSERM Faculté de Médecine de la Timone [FRANCE]
  • Gak, Eva
    Sheba Medical Center Genetics Institute [ISRAEL]
  • Laviola, Giovanni
    Instituto Superiore di Sanita [ITALY]
  • Levi, Giovanni
  • Cardoso, M. Cristina
    Max Delbrück Center Molekular Medicine [GERMANY]
  • Esteller, Manel
    Spanish National Cancer Center (CNIO) Molecular Pathology Programme, Cancer Epigenetic Laboratory [SPAIN]
  • Huppke, Peter
    Georg August University Pediatrics and Pediatric Neurology [GERMANY]
  • Russo, Silvia
    Instituto Auxologico Italiano Laboratorio di Biología Molecolare [ITALY]
  • Bienvenu, Thierry
    Institut Cochin INSERM U567 [FRANCE]
  • Broccoli, Vania
    San Raffaele Scientific Institute DIBIT [ITALY]