Q61H

Q61H is a missense mutation in members of the Ras family of small GTPases, defined by the substitution of histidine for glutamine at residue 61. This position lies in the catalytic region of Ras and plays a crucial role in the hydrolysis of bound GTP to GDP.

Biochemically, the Q61 residue participates in stabilizing the transition state and activating a water molecule for nucleophilic attack during GTP hydrolysis. Replacing glutamine with histidine disrupts this catalytic function, typically reducing the intrinsic GTPase activity of Ras and diminishing the effectiveness of GTPase-activating proteins (GAPs). As a result, Ras tends to remain in the GTP-bound, active state for longer periods, leading to sustained signaling.

Cellular signaling downstream of Q61H-mutant Ras is enhanced, with persistent activation of pathways such as the MAPK/ERK and PI3K-Akt cascades. This promotes cellular processes associated with oncogenesis, including proliferation, survival, and migration. The specific phenotypic consequences can vary depending on the Ras isoform (HRAS, KRAS, NRAS) and the cellular context.

Occurrence and significance: Q61H has been observed in various cancers as one of several activating Ras mutations. It is less common than some other Ras mutations (for example, at codons 12 and 13) but is still considered oncogenic. Detection typically relies on tumor DNA sequencing, which can inform prognosis and potential eligibility for targeted therapeutic strategies.

Clinical and research context: While there are no widely approved, mutation-specific inhibitors for Q61H as of now, Ras-driven cancers continue to be a focus of targeted therapy research. Approaches include strategies to inhibit Ras signaling more broadly or to target downstream effectors and regulators of Ras activity.