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Ricci et al. Vessel Plus 2021;5:31 https://dx.doi.org/10.20517/2574-1209.2021.28 Page 3 of 14

CCM1/KRIT1
The KRIT1 gene (OMIM #604214) is located on chromosome 7q21.2 and contains 16 coding exons that
[24]
encode for the Krev interaction trapped 1 (KRIT1) protein (UniProt #O00522). KRIT1 is a 736-amino acid
microtubule-associated protein, containing a NUDIX domain, multiple NPxY/F motifs, four ankyrin repeat
domains at the N-terminus, and one C-terminal FERM domain (band 4.1 ezrin radixin moesin
domain) [25,26] . Gene and protein structures are shown in Figure 1.

The NPxY/F motifs may be involved in dimerization and intramolecular folding of the KRIT1 protein
[26]
and are recognized by phosphotyrosine binding (PTB) domains. PTB domains are present on several
proteins, including the α-isoform of β1-integrin regulator integrin cytoplasmic adaptor protein 1
(ICAP1α) . Through the same PTB domain, ICAP1α can interact with KRIT1 or with integrins. In the
[27]
latter case, the interaction causes the activation of β-integrin signaling and stimulates angiogenesis. Thus,
KRIT1 may act as a modulator of ICAP1α activity, by competing with β-integrin interaction . The NpxY/F
[28]
motifs also interact with other known proteins: sorting nexin 17 (SNX17), a modulator of endocytosis and
[29]
intracellular trafficking ; the Kelch family protein Nd1-L, showing a role in ROS (Reactive Oxigen Species)
homeostasis ; and the PTB domain present in Malcavernin, which in turn binds to PDCD10 and acts as a
[30]
bridge between KRIT1 and PDCD10 .
[26]
The ankyrin repeats in KRIT1, present in many proteins, mediate inter- and intra-molecular interactions.
They are involved in different cellular processes, such as gene transcription, cell cycle control, and
organization of the cytoskeleton . Finally, the FERM domain of KRIT1, composed of three subdomains
[31]
F1-F3, interacts with the NPxY/F motif on the cytoplasmic face of transmembrane receptors and with
[24]
[32]
Rap1. Association with Rap1 relocalizes KRIT1 from microtubules to cell junction membranes .
KRIT1 pathogenic variants
More than 300 pathogenic variants have been reported so far in the HGMD . These variants are present
[14]
across the whole gene, with no evidence of hot spot regions [Supplementary Table 1]. The majority of them
are substitutions, deletions, and insertions [Figure 2A], mainly located in the coding and splicing regions
[Figure 2B]. They are splice junctions, frameshift, nonsense, and missense variants, often affecting the
splicing process [Figure 2C] . Gross deletions, involving one or more exons, until the complete lack of the
[12]
gene, have also been reported.

Regardless of the type of mutation, pathogenic variants result in a premature termination of translation,
introducing an early termination codon, generating an unstable mRNA, or truncated KRIT1 proteins totally
[33]
or partially lacking in the putative Rap1-interacting region . This evidence supports the hypothesis of a
loss-of-function mechanism , which can lead to CCM lesion genesis. Loss of KRIT1 alters cellular
[34]
signaling and behavior. Moreover, endothelial cells acquire stem cell-like features and become more
proliferative and invasive .
[35]
CCM2/MGC4607
The CCM2/MGC4607 gene (OMIM #607929) is located on chromosome 7p13 and contains 10 coding
[24]
exons . CCM2 encodes for CCM2/Malcavernin (UniProt #Q9BSQ5), a 444-amino acid protein that
contains a predicted N-terminal PTB domain and a C-terminal Harmonin homology domain (HHD)
[Figure 3].

Through the PTB domain, Malcavernin binds to KRIT1 and regulates its cellular localization [26,36] . The HHD
domain is involved in the interaction with the protein kinase MEKK3 (MAP3K3) . As a result of this
[37]