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Page 2 of 23 Padarti et al. Vessel Plus 2018;2:21 I http://dx.doi.org/10.20517/2574-1209.2018.34

Even in patients affected by disease within the same family, there is a wide range of clinical presentations which
are primarily determined by the number and size of lesions. This suggests that additional genetic modifiers or
non-genetic factors may exist in the pathogenesis of the disease . As of date, CCM1 (KRIT1) on chromosome
[6]
7q, CCM2 (MGC4607/OSM/Malcavernin) on chromosome 7p, and CCM3 (PDCD10/TFAR15) on chromosome
3q are genes that are known to cause the familial form of CCM. It is estimated that 1 in 200 people harbor a
potential mutation in one of three CCM genes and the frequency increases to 1 in 70 in the Hispanic population .
[7]
An epidemiological study showed that 94% of all familial forms and 57% of all sporadic forms of CCM result
from mutations in one of these three genes , raising a possibility that mutations in other genetic loci might
[8]
exist [9,10] . Recently, many polymorphisms were found in patients with the sporadic form of the disease, further
strengthening the argument that the presence of other genetic risk factors that can contribute to the sporadic
cases of CCM is possible . However, endeavors to identify novel CCM loci have so far failed. It was proposed
[11]
that the lesions formed in the familial form through a “second hit” mutation while sporadic vascular lesions
occurred due to somatic mutations in both alleles caused by mutagens, radiation, or other factors. However, the
familial form has an increased propensity for lesions since only one functional allele is present. Therefore, the
familial form characteristically develops neurological manifestations earlier with multiple brain lesions, while
the sporadic form develops late neurological manifestation with solitary brain lesions [12,13] .

As mentioned earlier, at least one of these three genes (CCM1, 2, 3) is disrupted in most CCM cases in
humans . The three CCM proteins interact to form a protein complex [15-19] which further interacts with
[14]
other proteins [19-22] . This CCM protein complex, referred to as the CCM signaling complex (CSC) , has
[19]
affinity toward a wide range of ligands and such interactions are involved in cell adhesion, migration, and
apoptosis [15,16,19,23-25] . Current evidence suggests that as core CSC proteins, CCM proteins act as scaffolds
for many signal molecules and spatiotemporally regulate localization and activity of these proteins, with
none possessing innate catalytic activity . Homozygous mutations in any of the three CCM proteins are
[26]
nonviable, indicating their essential role in biogenesis as phenotype suppressors [11-13] . We will mainly focus
on these three core CSC proteins in this review.

CLINICAL PRESENTATION
All forms of human CCM mutations induce lesions in the CNS. These lesions are used to follow the course
of disease (clinically symptomatic or not) both in the laboratory and in the clinical setting through MRI. A
CCM variant observed in the skin tissue is known as hyperkeratotic cutaneous capillary venous malformation
(HCCVM) . Other cutaneous manifestations include café-au-lait spots, cutaneous venous malformation,
[27]
and cavernous hemangiomas [28,29] . Genetic analysis showed that HCCVMs were only found in patients with
a frameshift mutation resulting in a premature stop codon in exon 1 of CCM1. CCM1 mutations have also
been associated with hepatic angiomas . As for clinical manifestation, CCM1 and CCM2 familial forms are
[30]
similar while CCM3 familial form has several unique characteristics. CCM1 and CCM2 mutations result in
spinal cavernous angiomas . Unlike CCM1 and CCM2 mutations which manifest later, CCM3 mutations
[28]
manifest as early as age 20 . CCM3 cases have the heaviest disease burden characterized by numerous CNS
[31]
lesions, with an increased risk of bleeding [32,33] . In addition to cutaneous manifestations with premature
termination codon mutation in exon 1 of CCM1 , CCM3 mutation cases also present scoliosis , mental
[33]
[34]
retardation , and meningiomas . No other genetic locus for familial forms of CCM has been identified
[31]
[35]
yet . However, there are still patients suffering from CCM with normal CCM1, CCM2, and CCM3 genetic
[36]
screen results. Even utilizing next-generation sequencing to screen the whole genome of CCM patients with
known and unknown mutations, no causative mutation among all three CCM loci was detected for these
CCM patients , further suggesting the existence of a potential new CCM locus.
[37]
PROTEIN STRUCTURE
CCM1 is the largest of the three CCM proteins (736 amino acids) and the most common CCM gene mutated [7,38] .
50% of all familial forms of CCM are due to mutations of CCM1 [36,39] . The penetrance of CCM1 mutation