MINIREVIEW SERIES

Recent insights into cerebral cavernous malformations

Eva Faurobert
Institute Albert Bonniot, Grenoble, France

In the general population, 1 in 200–250 individuals car-
ries cerebral cavernous malformations (CCM). These
individuals may be unaware of this until they begin to
suffer from diverse neurological clinical manifestations
like seizures or stroke. The vascular malformations,
characterized by abnormally enlarged thin-walled
vessels lacking smooth muscle support, are prone to
hemorrhage. The disease can be either sporadic or
inherited. Over the last 10 years, three CCM genes
(CCM1–3) have been related to the disease and their
discovery has opened the way to an understanding of
the disease and pointed to three novel and unsuspected
players in angiogenesis.
In this minireview series, we describe recent progress
in analyzing new data on the genetics of the disease and
the regulation of molecular pathways. We have directed
our efforts into surveying what is known about the
genetics of the disease, what advances have been made
possible by animal models, and the nature of the emerg-
ing signaling pathways regulated by CCM proteins.
The first minireview by Riant et al. deals with the
genetics of the disease. Almost all the germline muta-
tions encountered in CCM patients are loss-of-function
mutations. Because CCM disease is autosomal domi-
nant, what makes lesions occur focally and in multiple
sites in the familial cases? Several groups have shown
that a ‘two-hit’ mechanism is operating. A somatic
mutation, likely acquired in the embryonic or postnatal
period, adds to the germline mutation resulting in the
complete loss of the two alleles. Interestingly, somatic
mutations occur only in endothelial cells and not in the
intervening neural tissue. Not all endothelial cells of a
lesion carry the somatic mutation. Therefore, it seems
that lesions are comprised of a mosaic of wild-type and
mutant endothelial cells.
The second minireview by Chan et al. is dedicated to
animal models of CCM proteins. Zebrafish and mouse
models have been very valuable and complementary in
deepening our understanding of the molecular mecha-
nisms underlying CCM pathology. Importantly, zebra-
fish studies have identified a novel gene named heg and
the small GTPase gene rap1b as genetic interactors of
Ccm1 and Ccm2 genes. Mutant embryos display major
developmental vascular defects leading to death at mid-
gestation. Brain seems to be a privileged anatomic site
for vascular malformations. Because CCM proteins are
more abundantly expressed in neural tissue than in
endothelium, an important issue was to determine
whether the primary defect lies in neural or endothelial
cells. Two groups have obtained proof of an absolute
requirement for CCM2 in the endothelium during
development, whereas neural expression of CCM2 is
not required. Future research will be aimed at generat-
ing viable animal models that more faithfully reproduce
the human phenotype of CCM during aging. These
models would indeed be very valuable for testing phar-
macological therapies.
The last minireview by Faurobert and Albiges-Rizo
deals with the molecular mechanisms of CCM disease.
By gathering information on the biochemistry and cel-
lular biology of CCM proteins and their partners, it
highlights the diverse signaling pathways possibly regu-
lated by these proteins. CCM proteins are likely to
assemble into a large intracellular signaling hub that
controls endothelial cell–cell junctions, cell shape
remodeling and cell adhesion to the extracellular
matrix. A global picture remains hard to define, but
future findings on CCM will certainly teach us much
about blood vessel morphogenesis.
Many new insights have been brought to the CCM
research field over the past 2 years. Ongoing studies
from very different approaches promise many more
surprises and successes for researchers and new hope
for patients.

Eva Faurobert is a CNRS researcher at the Institute Albert Bonniot, Université Joseph Fourier, Grenoble, France. She has
previously worked on G-protein signaling in the laboratory of Marc Chabre and Pierre Chardin in Sophia Antipolis, France and
during her post-doc in James Hurley’s laboratory in Seattle, WA, USA. Two years ago, she joined Corinne Albiges-Rizo’s group
to focus on the dialogue between the endothelial cell and its extracellular matrix during angiogenesis. Her interest in joining
Albiges-Rizo’s group was to combine classical cellular biology with animal models and innovative biophysical approaches.

doi:10.1111/j.1742-4658.2009.07534.x

FEBS Journal 277 (2010) 1069 Journal compilation ª 2010 FEBS. No claim to original French government works 1069