A Drosophila model for Costello Syndrome caused by Ras mutation K117R.

Area of Science:

• Developmental Biology
• Genetics
• Pharmacology

Background:

• RASopathies are developmental disorders caused by Ras pathway hyperactivation.
• Costello syndrome, a RASopathy, is linked to HRas gain-of-function mutations, commonly at G12/G13, but also rare sites like K117.
• Existing Drosophila models often use common cancer mutations (e.g., G12V) or different Ras isoforms.

Purpose of the Study:

• To characterize the phenotype of a rare Ras gain-of-function mutation (K117R) in Drosophila.
• To evaluate the efficacy of Ras pathway inhibitors (Trametinib, Rigosertib) in a novel Drosophila RASopathy model.
• To investigate the signaling pathways involved in Ras K117R-induced phenotypes.

Main Methods:

• Engineered the Ras K117R gain-of-function mutation in the Drosophila Ras sequence.
• Assessed phenotypes including lethality, body size, eye morphology, and wing vein development.
• Administered Ras pathway inhibitors Trametinib (MEK inhibitor) and Rigosertib (PI3K/Raf-ERK inhibitor).

Main Results:

• Constitutive Ras K117R expression increased lethality, reduced body size, and caused rough eyes and ectopic wing veins.
• Trametinib and Rigosertib suppressed lethality, but only Trametinib significantly affected wing vein phenotypes.
• Reduced body size was not rescued by either inhibitor, suggesting Raf/PI3K-independent mechanisms.

Conclusions:

• The Drosophila Ras K117R model recapitulates key aspects of RASopathies and provides a platform for mechanistic studies.
• Lethality and wing vein phenotypes are partially dependent on Raf-ERK and potentially PI3K signaling.
• Small stature in this model appears independent of canonical Raf- and PI3K-mediated signaling.