Krev interaction trapped protein 1 (KRIT1) (KRIT1)

Krev interaction trapped protein 1 (KRIT1), also known as CCM1, is a multi-domain scaffold protein essential for maintaining the structural integrity of the vascular endothelium [1]. It functions by interacting with the small GTPase Rap1 and forming a complex with CCM2 and CCM3 to regulate endothelial cell-cell junctions and suppress the RhoA/ROCK signaling pathway [2]. Mutations in the KRIT1 gene or its mRNA, typically resulting in loss-of-function, are the primary cause of Cerebral Cavernous Malformations (CCM), a condition characterized by enlarged, leaky capillary-like vessels in the central nervous system [4]. The KRIT1 mRNA is a specific focus for therapeutic intervention, particularly through the use of read-through agents like Ataluren which target premature termination codons to restore protein expression [3]. Additionally, KRIT1 plays a vital role in modulating cellular redox homeostasis and autophagy, protecting cells against oxidative stress-induced damage [2]. Because KRIT1 deficiency leads to hyperactivation of Rho-kinase, pharmacological strategies often involve indirect targeting with ROCK inhibitors like Fasudil to stabilize the vasculature [3]. Monitoring KRIT1 mutation status and lesion progression via MRI remains the standard for clinical management and patient selection in emerging trials [4].

Other names

CCM1Cerebral cavernous malformations 1 proteinKrev interaction trapped 1

Restoration of functional protein levels via translational read-through of nonsense mutations in mRNA or indirect inhibition of the hyperactive downstream RhoA/ROCK signaling pathway.