Joint Transnational Call 2009 (JTC2009)
RASopathies constitute an emerging family of disorders affecting development and growth. This group of diseases includes Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and an increasing number of other clinically related conditions sharing dysregulation of RAS signaling as common pathogenetic mechanism. Clinical manifestations of RASopathies include postnatal reduced growth, a wide spectrum of cardiac defects, facial dysmorphism, ectodermal and skeletal anomalies, variable cognitive deficits, and increased risk for certain hematologic malignancies and other pediatric cancers. Most of these conditions are genetically heterogeneous, and the underlying genetic cause has not been identified yet for a still large fraction of cases. Understanding the molecular bases of RASopathies is a requisite to diagnose and treat these disorders effectively as well as for a more efficient patient management and risk assessment.
Major goals of this project were to understand the molecular events implicated in disease pathogenesis, assess the prevalence and diversity of RASopathy gene mutations and their associated phenotypic diversity, delineate clinically relevant genotype-phenotype correlations, and provide innovative tools for early diagnosis and the development of therapeutic intervention. Major findings of this Consortium follow.
A gene candidacy approach was used to discover three novel RASopathy genes (NRAS, CBL and RRAS). Biochemical and functional characterization of disease-causing mutations has provided novel insights on pathogenesis. Specifically, these studies have delineated the consequences of Noonan syndrome and LEOPARD syndrome causative PTPN11 mutations on SHP2 function and intracellular signaling. Research has also been directed to dissect the differential structural and functional impact of disease-causing KRAS and HRAS mutations. Finally, the partners of this Consortium have contributed significantly to a number of multicentric, clinically oriented studies, making available new data that will help clinicians towards a timely diagnosis and efficient patient management, as well as to research directed to the development of new in vitro tools for future translational research studies.
- Tartaglia, Marco (Coordinator)
Instituto Superiore di Sanita Ematologia, Oncología e Medicina Molecolare [ITALY]
- Cavé, Hélène
CHU Robert Debré Université Denis Diderot Paris VII Genetics [FRANCE]
- Zenker, Martin
University Hospital of Erlangen University of Erlangen-Nuremberg [GERMANY]
- Rayna, Patrick
INSERM U563 Centre de Physiopathologie de Toulouse-Purpan [FRANCE]
- Ahmadian, Reza
Heinrich Heine Medical Center Biochemistry and Molecular Biology [GERMANY]
- Elgersma, Ype
Erasmus University Center (EMC) Neuroscience [NETHERLANDS]