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

Figure 4. Mutation distribution of pathogenic CCM2 variants as reported so far in the HGMD [14] : (A) distribution by type at DNA level;
(B) distribution by DNA location; and (C) distribution by type at protein level (please note that in this case the term “missense” is used
to define variants so classified in the original studies, without information regarding their impact on splicing process). The classification
of variants has not been independently verified by the authors.

aberrant splicing with a consequent frameshift. The only pathogenic missense variants that do not alter the
splicing process have been identified within the PTB domain . These variants abolish the interaction
[39]
between Malcavernin and KRIT1, strongly suggesting a causative role in CCM disease [40,41] .

As in the case of the KRIT1 gene, deletions involving whole gene or a large part of it have been described. A
77.6-kb deletion spanning from exon 2 to exon 10 is a common founder mutation in the United States
population .
[42]
CCM3/PDCD10
The PDCD10/CCM3 gene (OMIM #609118), located on chromosome 3q26.1, is a highly conserved gene
[24]
containing seven coding and three non-coding exons . It encodes the programmed cell death protein 10
(PDCD10), a 212-amino acid protein (UniProt #Q9BUL8) that contains a dimerization domain at the N-
terminus, and a C-terminal focal adhesion targeting (FAT)-homology domain [Figure 5].

The dimerization domain allows PDCD10 to form a dimer. The FAT-homology domain stabilizes the
PDCD10 protein and interacts with Malcavernin and with several other signaling proteins [43,44] . Among
[38]
these are molecules involved in VEGF signaling, which is fundamental for vascular development [45,46] . In
addition, PDCD10 plays a critical role in the regulation of the angiogenesis through DLL4-Notch
signaling [45,47] .

It is known that PDCD10 is involved in apoptosis: its overexpression induces the activation of caspase 3 and
increases cell death [48,49] . Thus, in the presence of PDCD10 mutations, CCM disease may originate from a
[50]
modification of the apoptotic process, which alters the equilibrium between neural cells and endothelium .
PDCD10 pathogenic variants
More than 70 pathogenic variants of the PDCD10 gene are present in the HGMD [Supplementary Table 3],
including small and gross deletions, substitutions, insertions, and duplications [Figure 6A]. They are mainly
located in the coding region, often between exon 5 and exon 7. In this case as well, frameshift, nonsense,
and missense variants have been identified, all leading to a premature stop codon. Moreover, the presence
of large deletions may result in the lack of protein production [Figure 6B and C].

Considering that the pathogenic variants detected so far are loss of function variants, haploinsufficiency and
somatic loss of heterozygosity have been proposed as pathogenic mechanisms for CCM3 [23,51] .

PHENOTYPE CORRELATIONS BY GENE
An important feature of CCM is the heterogeneity of the phenotypes. Variable expressivity is observed
within affected individuals belonging to the same family and between families linked to the same mutation.