Bioenergetics of RASopathies and treatment opportunities (translational)

Little is known on the molecular mechanisms linking RAS hyperactivation and altered organ development. RASopathies affect approximately 1/1000 human birth but no therapy is available. We discovered that one pathophysiology molecular mechanism underpinning the Costello syndrome is alteration of the energy sensing AMPK pathway. Our work is based on the analysis of Costello Syndrome derived patients cell lines, the Costello mice (HRASG12S) and cell models expressing hyperactive forms of HRAS (G12A/S/V). We are also currently investigating patient’s samples from patients with Neurofibromatosis type 1 (NF1) using a similar combination of Omics and Bioenergetics approaches. The two projects, Costello and NF1, are performed in close collaboration with rare diseases patients associations and with the departments of medical genetics and of dermatology of Bordeaux University Hospital.

Mitochondrial implications in RASopathies. The proteins commonly mutated in RASopathies are color-coded to represent different syndromes: Noonan Syndrome (NS; blue), Noonan Syndrome with Multiple Lentigines (NSML; orange), Costello syndrome (CS; yellow), Cardio-Facio-Cutaneous Syndrome (CFC; green), Capillary Malformation -Arteriovenous Malformation Syndrome (CM-AVM; red), NeuroFibromatosis type 1 (NF1; magenta) and Legius syndrome (LS; turquoise).

Contributing Members

R. Rossignol

Project publications

RAS signaling in energy metabolism and rare human diseases. Biochim Biophys Acta Bioenerg. 2018 Sept. 1859(9):845-867 [Review]

Laetitia Dard PhD Thesis [19 December 2018]

Dard et al. mir-221* – Dependent inhibition of AMPKα2 by mutant HRAS constrains oxidative phosphorylation in Costello syndrome (submitted)

Project funding

ANR Cosmit Project (DS0411)
Grant by the Costello and CFC French Patients Association.
Grant by the French Association on Neurofibromatosis Type 1.