MINIREVIEW

Recent insights into cerebral cavernous malformations:

the molecular genetics of CCM
Florence Riant1,2, Francoise Bergametti2, Xavier Ayrignac2, Gwenola Boulday2 and Elisabeth
Tournier-Lasserve1,2
1 AP-HP, Hôpital Lariboisière, Laboratoire de Génétique, Paris, France
2 INSERM UMR-S 740, Université Paris 7 Diderot, France

Keywords
angiogenesis; CCM1; CCM2; CCM3;
cerebral cavernous malformations; cerebral
hemorrhage; KRIT1; PDCD10; stroke;
vascular malformations
Correspondence
E. Tournier-Lasserve, INSERM UMR-S 740;
Université Paris7 Diderot, 10 Avenue du
Verdun, 75010 Paris, France
Fax: +33 157278594
Tel: +33 157278593
E-mail: tournier-lasserve@univ-paris-diderot.fr
Cerebral cavernous malformations (CCM) are vascular lesions which can
occur as a sporadic (80% of the cases) or familial autosomal dominant
form (20%). Three CCM genes have been identified: CCM1 ⁄ KRIT1,
CCM2 ⁄ MGC4607 and CCM3 ⁄ PDCD10. Almost 80% of CCM patients
affected with a genetic form of the disease harbor a heterozygous germline
mutation in one of these three genes. Recent work has shown that a two-
hit mechanism is involved in CCM pathogenesis which is caused by a com-
plete loss of any of the three CCM proteins within endothelial cells lining
the cavernous capillary cavities. These data were an important step towards
the elucidation of the mechanisms of this condition.

(Received 1 August 2009, revised 4

November 2009, accepted 4 December
2009)

doi:10.1111/j.1742-4658.2009.07535.x

Introduction
Cerebral cavernous malformations (CCM ⁄ OMIM
116860) are vascular lesions histologically character-
ized by abnormally enlarged capillary cavities with-
out intervening brain parenchyma. From large series
based on necropsy and ⁄ or magnetic resonance imag-
ing (MRI) studies, their prevalence in the general
population has been estimated to be close to 0.1–
0.5%. Most CCMs are located within the central
nervous system but they sometimes affect either the
retina or the skin [1].
CCM occur both sporadically and in a familial
context. The proportion of familial cases has been esti-
mated to be as high as 50% in Hispano-American
CCM patients [2] and close to 10–40% in Caucasian
patients [1]. The CCM pattern of inheritance is
autosomal dominant with incomplete clinical and
neuroradiological penetrance. The presence of multiple
lesions on cerebral MRI is one of the main features of
familial CCM which is an evolutive condition as
assessed by the strong correlation between patient age
and the number of lesions (Fig. 1) [1–3]. The average
age-of-onset is around 30 years but symptoms can
start in early infancy or in old age. The main
symptoms include seizures and cerebral hemorrhages.
Sporadic cases most often have a single lesion on
MRI, are not inherited and do not carry a CCM gene
germline mutation. However, some CCM patients who
have multiple MRI lesions do not have any known
clinically affected relative and therefore present as
sporadic cases. Combined use of clinical and MRI

Abbreviations
CCM, cerebral cavernous malformations; MRI, magnetic resonance imaging; PDCD10, Programmed Cell Death 10.

1070 FEBS Journal 277 (2010) 1070–1075 ª 2010 The Authors Journal compilation ª 2010 FEBS
F. Riant et al.
Fig. 1. Cerebral magnetic resonance imaging of a 4-year-old familial
CCM patient. Multiple CCM lesions are shown (arrowheads) as
well as a cerebral hemorrhage (arrow).
screening with molecular testing has helped to clarify
what might have first seemed confusing [1].
Three CCM genes have been mapped and identified
in the recent years. These molecular genetics data have
provided useful information for clinical care of the
patients and were an important step towards the
understanding of the mechanisms of this disorder. This
minireview summarizes the advances in CCM molecu-
lar genetics and the remaining gaps in this field. In
addition to the identification of CCM genes, a number
of recent biochemical in vitro studies and in vivo CCM
animal model studies have helped to unravel the func-
tional roles of these proteins and are be the focus of
the two accompanying minireviews by Faurobert and
Albiges-Rizo [4] and Chan et al. [5].
Fig. 2. CCM loci and genes. Three CCM
genes have been mapped and identified to
date, CCM1 ⁄ KRIT1, CCM2 ⁄ MGC4607 and
CCM3 ⁄ PDCD10. In 22% of CCM cases
with multiple lesions, no mutation is
detected in these three genes using
currently available technologies.
FEBS Journal 277 (2010) 1070–1075 ª 2010 The Authors Journal compilation ª 2010 FEBS
CCM molecular genetics
CCM genes germline mutations
Genetic linkage analyses mapped three CCM loci to
chromosome 7q (CCM1), 7p (CCM2) and 3q (CCM3)
[6,7]. A strong founder effect has been oberved in His-
pano-American CCM patients with most families
linked to the CCM1 locus [8]. In Caucasian families,
the proportions of families linked to each CCM locus
were 40% (CCM1), 20% (CCM2) and 40% (CCM3)
[7]. The three genes located at these loci have now
been identified (Fig. 2) [9–13].
The CCM1 gene contains 16 coding exons which
encode for Krit1, a 736-amino acid protein containing
three ankyrin domains and one band 4.1 ezrin radixin
moesin (FERM) domain. CCM2, a 10-exon gene,
encodes for the MGC4607 protein, also called malc-
avernin, which contains a phosphotyrosin binding
domain. CCM3 includes seven exons which encode for
Programmed Cell Death 10 (PDCD10), a protein with-
out any known conserved functional domain, which
may be involved in apoptosis. Considerable progress
has been made recently in understanding the biochemi-
cal pathways in which those proteins might be
involved (see Faurobert and Albiges-Rizo [4]).
More than 150 distinct CCM1 ⁄ CCM2 ⁄ CCM3 germ-
line mutations have been published to date [9–23].
Those mutations were highly stereotyped because
almost all led to a premature termination codon
through different mechanisms including nonsense,
splice-site and frameshift mutational events, as well as
large genomic rearrangements. These data strongly
suggest that a loss of function, through mRNA decay
of the mutated allele, is the most likely pathophysio-
logical mechanism involved in CCM patients. Only
four ‘missense’ mutations within CCM1 have been
reported to date; interestingly, all of them actually
activated cryptic splice sites and led to an aberrant
splicing of CCM1 mRNA and a frameshift with a
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CCM molecular genetics
premature stop codon [10,24]. The only known mis-
sense mutation which did not affect splicing has been
located within the C-terminal part of the phosphotyro-
sin binding domain of CCM2 [12]. This mutation has
been shown to abolish the interaction of CCM2 and
CCM1, strongly suggesting its causality [25]. Only four
inframe deletions have been reported: two affect ex-
ons 17 and 18 of CCM1, one deletes exon 2 of CCM2
and one deletes exon 5 of CCM3. The last two dele-
tions have been used to map potential relevant interac-
tion domains of CCM2 and CCM3 [23,26]. However,
it is not known if these putative truncated proteins
were indeed produced and stable in vivo.
Sequencing of all coding exons of the three CCM
genes and search for genomic rearrangements using
cDNA and ⁄ or quantitative multiplex PCR such as
multiplex ligation-dependent probe amplification in
Caucasian non-Hispano-American CCM multiplex
families led to the identification of the causative muta-
tion in 95% of the families [23,27]. Approximately
72% of multiplex families harbored a mutation in
CCM1, 18% in CCM2 and 10% in CCM3. The
CCM3 proportion was much lower than expected,
based on previous linkage data which suggested that
40% of CCM families were linked to the CCM3 locus.
The mutation detection rate was lower in sporadic
cases with multiple lesions, ranging from 45% to 67%
[22,23,27]. Most of these sporadic cases with multiple
lesions had either inherited their mutation from one of
their asymptomatic parents because of incomplete pen-
etrance or had a de novo mutation. Sporadic cases with
multiple lesions in whom no mutation was detected are
nevertheless most likely affected by a genetic form of
the disease. Several hypotheses may be raised to
explain the absence of any detected mutation, includ-
ing a somatic mosaicism of a de novo mutation which
occured during gestation and is not detectable in DNA
extracted from peripheral blood cells. It will be impor-
tant to solve this in the future because it is of interest
for genetic counseling [1]. With regard to sporadic
CCM cases with a unique lesion on cerebral MRI, no
mutation was detected in reported series [16,17]. Com-
bination of these data with those obtained in familial
CCM strongly suggests that sporadic cases with a
unique lesion who would harbor a germline mutation
are most likely very rare.
Haplotyping data strongly suggested a founder effect
in the Hispano-American CCM population; this was
confirmed by the detection of a Q455X stop codon
mutation in CCM1 in most families with this ethnic
background [10]. Recurrent mutations have also been
identified in a few additional populations [21,28]. How-
ever, in most cases, despite their highly stereotyped
1072 FEBS Journal 277 (2010) 1070–1075 ª 2010 The Authors Journal compilation ª 2010 FEBS
F. Riant et al.
consequences, germline CCM mutations are ‘private’
mutations present in only one or very few families.
Biallelic somatic and germline
mutations in CCM lesions
Based on the autosomal dominant pattern of inheri-
tance of CCM and the presence of multiple lesions in
familial CCM, contrasting with the detection of a sin-
gle lesion in nonhereditary cavernous angiomas, it has
been proposed that a second hit affecting the wild-type
allele might be involved in CCM lesions pathophysiol-
ogy, as reported previously in retinoblastoma or other
vascular malformations [29,30]. According to this
hypothesis, CCM formation would be caused by a
complete loss, within affected cells, of the two alleles
of a given CCM gene. Loss of one of the alleles (first
hit) would be the result of a germline mutation and
loss of the second allele (second hit) will occur somati-
cally.
This hypothesis is not easy to test because of the
heterogeneous cellular nature of CCM lesions and the
very limited number of endothelial cells lining the cap-
illary cavities. Indeed, direct sequencing of the DNA
extracted from a heterogeneous lesion may not detect
the mutation depending of the proportion of the cells
which harbor this mutation within the lesion. This
approach was initially used to screen CCM lesions
from both sporadic and a few familial patients and did
not detect any somatic mutation except in one spo-
radic case [31]. In this latter case, two CCM1 missense
mutations, F97S and K569E, were detected in the
CCM lesion and were shown to be absent in the blood
of the patient. However, the data were difficult to
interprete because of the nature of the mutations
which were not truncating mutations (a possible aber-
rant splicing effect of these two mutations was not
investigated) and the fact that the biallelism of these
mutations was not explored.
In 2005, Gault et al. reported the first biallelic
CCM1 germline and somatic truncating mutation in a
CCM lesion, strongly supporting this ‘two-hit’ mecha-
nism in the formation of lesions, at least in CCM1
patients; they demonstrated recently that this second
hit occurred within the endothelial cells [32,33].
Biallelic somatic and germline mutations in each of
the three CCM genes were recently reported by Akers
et al. [34]. These authors amplified and sequenced a
large number of clones from 10 CCM lesions resected
from patients harboring a heterozygous germline muta-
tion in either CCM1 (two patients), CCM2 (five
patients) and CCM3 (two patients). One CCM lesion
was analyzed for each patient. They were able to
F. Riant et al.
convincingly establish the presence of a biallelic
somatic and germline deleterious mutation in four of
these lesions from two CCM1 patients, one CCM2
patient and one CCM3 patient. The proportion of
amplicons carrying the somatic mutation ranged from
4% to 16%. None of these mutations was detected
through direct sequencing of lesion DNA, emphasizing
the lack of sensitivity of direct sequencing of lesion
DNA. These data established the existence of biallelic
somatic and germline mutations, whatever the nature
of the CCM gene involved, at least in some lesions.
No mutation was detected in the six remaining lesions.
Several hypotheses may be raised to explain this
absence of mutation including the incomplete sensitiv-
ity of this type of approach which would miss a second
hit consisting in either large genomic deletions and ⁄ or
epigenetic silencing mechanisms.
Interestingly, the authors showed, using laser cap-
ture, that the somatic mutation occurred in endothelial
cells and not in the intervening neural tissue. The pro-
portion of endothelial cells which harbor the somatic
mutation was estimated in one lesion and shown to be
close to 30%, suggesting the mosaicism of this somatic
mutation. These data are in agreement with those
obtained very recently with an immunohistochemistry-
based approach which showed a mosaic loss of expres-
sion of CCM proteins in endothelial cells lining CCM
caverns [35]. This question would, however, require
additional investigations. It would also be important
to analyze several lesions from a given patient to test
for the presence of the same mutation in multiple
lesions. A unique somatic mutation has indeed been
detected in multifocal lesions in another hereditary
vascular condition suggesting a common origin for
abnormal endothelial cells lying in distant sites [36].
Altogether these data strongly suggest that CCM, as
several other hereditary vascular conditions, show a
paradominant inheritance. It remains to determine
when do occur the somatic, second hit, events.
Are there additional CCM genes?
Previous linkage data obtained on 20 large North
American families suggested that the three CCM loci
on 7p, 7q and 3q would most likely account for all
CCM families [7]. However, despite extensive screening
of exonic sequences for point mutations and deletions,
no mutation was detected in 5% of familial CCM
cases and a larger proportion of sporadic cases wth
multiple lesions [27]. In addition, the proportion of
families showing a mutation within PDCD10 (10%) at
the CCM3 locus on chromosome 3q25, was much
lower than expected based on linkage data (40%).
FEBS Journal 277 (2010) 1070–1075 ª 2010 The Authors Journal compilation ª 2010 FEBS
CCM molecular genetics
Several mutually nonexclusive hypotheses may
explain these data such as: (a) the existence of muta-
tions affecting cis-regulatory elements located at long
distances from known CCM transcription units; (b)
epigenetic silencing of these three genes; and (c) the
existence of additional nonidentified CCM genes, one
of which is possibly located close to PDCD10.
Recently, an additional gene, Zona Pellucida-like
Domain containing 1 (ZPLD1), has been reported to be
disrupted in a CCM patient harboring a balanced
translocation between chromosome X and chromo-
some 3q [37]. ZPLD1 is located on chromosome three
centromeric to PDCD10. The expression of the mRNA
in lymphoblastoid cell lines of the patient was shown
to be significantly decreased suggesting that the inter-
ruption of this gene may be causal. However, the same
authors screened this gene in 20 additional CCM
patients without any mutation in CCM1 ⁄ CCM2 ⁄
CCM3 and did not detect any mutation. These data
suggest that either this gene is involved in very rare
CCM patients or its interruption does not cause
CCM but that the translocation present in this patient
deregulated the expression of a gene unidentified yet.
Additional work currently conducted in several
teams should help in the next future to identify
the molecular anomalies of CCM patients ‘without’
mutations.
Conclusions and future
The recent identification of the three CCM genes is an
important step towards the elucidation of the mecha-
nisms of this condition. It helped to clarify several fea-
tures of this condition including its incomplete clinical
and MRI penetrance as well as the molecular basis of
sporadic cases with multiple lesions. Additional large
series studies are needed to evaluate genotype–pheno-
type correlations (particularly the prognosis) depending
of the nature of the mutated gene. Several additional
questions, however, have to be adressed. What is the
nature of the molecular anomaly in familial CCM
cases in whom no mutation has been detected? Are
sporadic cases CCM patients with multiple lesions
showing a mosaicism for a germline mutation? Are
there modifying genes that may explain the intrafamil-
ial clinical variability? In addition to these questions,
one main challenge is to understand the mechanisms
of this condition. The recent identification of several of
the biochemical pathways involving CCM proteins as
well as the analysis of several fish and mouse CCM
animal models has already provided a number of clues
to this goal (see Faurobert and Albiges-Rizo [4] and
Chan et al. [5]).
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