RASopathies

The RASopathies is a group of developmental disorders including Noonan, cardiofaciocutaneous, Costello, Legius and neurofibromatosis type 1 syndromes. Shared manifestations include craniofacial dysmorphism, congenital heart disease, growth and ectodermal abnormalities, neurodevelopmental impairment and, in some entities, tumor predisposition. More info
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Genetics

Usually caused by dominant germline variants in RAS-MAPK components or regulators, including PTPN11, SOS1/2, KRAS, NRAS, RIT1, RAF1, BRAF, MAP2K1/2, HRAS, LZTR1 and NF1. Inheritance and biochemical effect are gene- and variant-specific.

Molecular Mechanism

Developmental phenotypes result from altered intensity, timing or tissue distribution of RAS-RAF-MEK-ERK signaling. Most variants increase pathway output, but the relevant signaling imbalance and therapeutic window differ substantially between genes and alleles.

Therapy

Care is syndrome- and organ-specific. MEK inhibitors are established for selected NF1-associated tumors and are being used experimentally or off-label for severe cardiac and lymphatic RASopathy manifestations. They are not a general treatment for all RASopathies and require careful safety and genotype consideration.

CCP Activity

In collaboration with Dr. Pavel Krejci at Masaryk University, the CCP performs mechanistic studies and small-molecule testing in genetically defined RASopathy models. The aim is allele-aware selection of pathway modulators.

Mouse Models

  • B6.129S6-Krastm1Kshn/J (point mutation T58I in Kras, Noonan syndrome model)
  • B6.129S6-Krastm2Kshn/J (point mutation P34R in Kras, Cardiofaciocutaneous syndrome model)
  • B6.129S6(Cg)-Ptpn11tm4.2Bgn/FcrJ (point mutation Y279C in Ptpn11, LEOPARD syndrome model)