Human Molecular Genetics 2005 14(Review Issue 2):R269-R274; doi:10.1093/hmg/ddi262
© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The genetics of Fraser syndrome and the blebs mouse mutants
Ian Smyth1,2 and
Peter Scambler2,*
1Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK and
2Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
* To whom correspondence should be addressed. Email: p.scambler{at}ich.ucl.ac.uk
Received June 16, 2005; Accepted July 1, 2005
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ABSTRACT
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Fraser syndrome is a recessive multisystem disorder characterized
by embryonic epidermal blistering, cryptophthalmos, syndactyly,
renal defects and a range of other developmental abnormalities.
More than 17 years ago, the family of four mapped mouse blebs
mutants was proposed as models of this disorder, given their
striking phenotypic overlaps. In the last few years, these loci
have been cloned, uncovering a family of three large extracellular
matrix proteins and an intracellular adapter protein which are
required for normal epidermal adhesion early in development.
The proteins have also been shown to play a crucial role in
the development and homeostasis of the kidney. We review the
cloning and characterization of these genes and explore the
consequences of their loss.
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FRASER SYNDROME
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In 1962, George Fraser first described the syndrome bearing
his name (1
), and in more recent times, Slavotinek and Tifft
compiled an excellent summary of the condition. They described
several major and minor characteristics of Fraser syndrome (FS);
two major and one minor or one major and four minor features
being required to make a diagnosis (2
) (FS; MIM219000). The
major features include cryptophthalmos (in which skin covers
the globe of the eyes) (
90%), cutaneous syndactyly of varying
severity (
60%), abnormal or ambiguous genitalia (20%) and family
history of the disease (
40%) (Fig.
1). All cases described
so far are consistent with a recessive mode of inheritance.
Although the external eye defects are striking, posterior structures
are usually spared, and surgical intervention can result in
the ability to distinguish light and dark and some movement.
The disease is rare with a frequency of one in 10 000 still
births; however, FS may account for a higher proportion of early
term miscarriages.
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Figure 1. FS and the blebs mutants. The mouse blebs mutants were identified in a number of genetics screens. The most obvious feature of these animals is cryptophthalmia in which skin covers the globe of the eyes (A) (wild-type left and heb right). Many of the defects, such as cryptophthalmia and syndactyly, observed in these mice are mirrored in human FS (B). Many of these defects are caused by loss of epidermal adhesion during embryonic development. These blisters, or blebs, tend to form around the head, limbs and trunk (C) and can often become haemorrhagic late in gestation. The majority resolves prior to birth. The loss of adhesion occurs below the level of the BM lamina densa (D) (LD, lamina densa; LL, lamina lucida; epi, epidermis; bc, blister cavity). Defects in organogenesis are also characteristic of the belbs mutants as FS patients. For example, compared with wild-type E17 embryos (E) (Ki, kidney and Ad, adrenal gland), Grip1 mutant mice (F) display complete absence of kidney formation (images courtesy of Dr Ralf Adams, Cancer Research UK). Adult blebs mice also develop cystic renal disease as they age (G, asterisks). Three of the blebs mutants are caused by mutations in Fras1, Frem1 and Frem2, complex multidomain extracellular matrix proteins (H) (vWFC, von Willebrand factor type C; CSPG, chondroitin sulphate proteoglycan domain; CLECT, C-type lectin; CALXb, calcium exchange domain beta; TM, transmembrane domain).
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As a group, the minor features occur frequently, and we feel
that laryngeal stenosis and renal a/dysgenesis could be considered
as major features. Patients may also have skeletal defects,
pulmonary hyperplasia, ear malformations with conductive deafness,
orofacial clefting, gastrointestinal malformations and heart
defects. It has been estimated that 45% of cases are stillborn
or die within the first year, primarily because of pulmonary
or renal complications (3
). However, there is no reason to suspect
that those patients without these life-threatening complications
cannot live a normal lifespan.
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THE MOUSE ‘BLEBBING’ MUTANTS
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In 1988, Robin Winter (4
,5
) first speculated that the mouse
‘bleb’ mutants might be a murine equivalent of FS.
At that time, there were four mapped ‘bleb’ mutants
which localized to different chromosomes. Each line gave affected
homozygotes with combinations of eye abnormalities, renal anomalies
and syndactyly, with varying severity. The common embryological
phenotype of affected embryos was the presence of fluid filled
blebs arising at
12 days of gestation and occurring over the
extremities, eyes or hindbrain (Fig.
1). These blisters
subsequently became haemorrhagic and disappeared during late
gestation leaving the characteristic covering of the eye with
skin.
The first ‘bleb’ mutant to be described was myelencephalic blebs (my), which arose in an X-irradiation screen conducted by Little and Bagg (6). The blebbed mutation (bl) arose from offspring of a male irradiated with neutrons and, at least on the original undefined genetic background, appears to have the most severe phenotype with poor postnatal survival. It was suggested that a different mechanism might be operating during renal and skin development (7). The eye blebs (eb) mutation arose spontaneously, although histology gave little clue as to the basis for the abnormalities observed (8,9). In severe cases, mice failed to form the retina and the lens (10). The final mutant, head blebs (heb), arose spontaneously and was somewhat milder in severity than the eb and my mutants (11).
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IDENTIFICATION OF FS/BLEBBING GENES
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Early linkage analyses had established the approximate chromosomal
location of all the extant blebbing loci, although these mapping
experiments were not at a sufficiently high resolution to give
a confident indication of the respective locus in man. Subsequent
autozygosity mapping and gene sequencing in FS kindreds revealed
the loss of function mutations in a novel gene
FRAS1 (chromosome
4), the murine homologue being mutated in
bl (12
,13
). Targeted
mutation of the glutamate receptor interacting protein (
Grip1)
gene resulted in a phenotype closely resembling
bl (14
,15
).
Grip1 mapped to mouse chromosome 10, suggesting that it might
be the
eb gene, and an intragenic deletion of exons 10 and 11
confirmed this suspicion (15
). Concurrently, another blebbing
phenotype had been discovered in an ENU mutagenesis screen and
shown to be allelic with the
heb locus. Mutations in both alleles
were found in a gene encoding a protein with similarity to Fras1,
and the
heb gene was named
Frem1 (for
Fras-related, ECM) (16
).
Although analysis of families not linked to
Fras1 has identified
a few pedigrees compatible with linkage to the human homologues
GRIP1 (chromosome 12) and
FREM1 (chromosome 9), we have not
discovered any mutations within these genes.
The Frem2 and Frem3 genes were identified by genome database interrogation, Frem2 mapping precisely to a 1 cM interval defined by mapping the my locus on mouse chromosome 3. Subsequent complementation analysis showed that a gene trap mutation of Frem2 is allelic to the my mutation (17). Three FS families segregated a mutation in human FREM2 (E1972K), which substitutes a strongly conserved residue within the CALXß domain, a residue predicted to be important for calcium binding (discussed subsequently) (17). The Frem3 gene is not linked to any known blebbing locus, no mouse mutant is available and no mutations of FREM3 (chromosome 4) have been found in FS.
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STRUCTURE AND EVOLUTION OF THE ‘BLEB’ PROTEINS
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The extracellular blebs genes,
Fras1, Frem1 and
Frem2, encode
large multidomain proteins between 2172 and 4010 amino acids
in length (Fig.
1). Fras1 and Frem2 are transmembrane proteins,
whereas Frem1 contains a lectin type C domain at its C-terminus.
The hallmark feature of this family is the repeated
130 amino
acid chondroitin sulphate proteoglycan (CSPG) domain, whose
structure is thought to be similar to a cadherin fold (18
).
The proteins also incorporate one or more copies of the calcium
exchange ß domain (CALXß), a calcium chelating
motif present in a variety of calcium transporter proteins and
in other cell adhesion molecules (19
). These calcium binding
motifs are also structurally similar to cadherin domains (unpublished
data) and their likely functional importance is highlighted
by our identification of a disease causing
FREM2 CALXß
missense mutation in FS patients.
In addition to these protein elements, Fras1 also bears six von Willebrand factor type C (vWFC) and 14 cysteine rich partial furin motifs at its N-terminus. The established involvement of these domains in interaction with members of the TGF-ß growth factor family (20) has led to the suggestion that Fras1 might modulate their activity within the extracellular matrix (ECM) (13). The Fras and Frem genes are a relatively recently evolved family and form a monophyletic clade found only in deuterostomes. The most distant member of the family characterized to date is the sea urchin ECM3 gene which, on the basis of domain organization and sequence conservation, is an orthologue of Frem2. ECM3 is a major component of fibres which lie on the basal surface of the embryonic ectoderm and it is thought to orchestrate primary mesenchyme cell migration during gastrulation (21). Finally, Grip1 encodes a 7 PDZ domain cytoplasmic protein, which has been shown to interact with the most C-terminal residues of both Fras1 and Frem2. At least, in the case of Fras1, loss of Grip1 results in the failure of the protein to localize correctly to the basal membrane of keratinocytes in culture (15).
Clues to the function of the Frem and Fras genes are largely provided by studies of NG2, a gene widely expressed in partially differentiated or differentiating cells (22–26). The CSPG domains in NG2 are capable of diverse interactions with other extracellular components, many of which may have direct implications for Frem and Fras protein interactions. Various studies have demonstrated their interaction with collagens V and VI (27,28), basic fibroblast growth factor and platelet-derived growth factor (29). There is also mounting evidence to suggest that a soluble form of the protein can be generated by matrix metalloproteases (30,31). All of these studies raise the intriguing prospect that the Fras and Frem proteins may have the ability to regulate not only the assembly of structural components of the ECM, but also subtly modulate the activity of growth factors in the extracellular milieu.
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GENE EXPRESSION
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The blebs genes are expressed in a diverse pattern during embryonic
development. As a general rule, they are all expressed at high
levels in tissues in which a differentiating and remodelling
epidermis is interacting with an underlying mesenchyme (Fig.
2),
lending credence to the concept that the proteins play both
structural and developmental roles during tissue differentiation.
With only a few exceptions, the expression of
Frem1 is restricted
to the mesenchymal components of these structures, whereas
Frem2/
Fras1 and
Grip1 are expressed in the epithelial specializations. In
the developing skin,
Fras1 is expressed very strongly throughout
the developing epidermis (12
,13
), whereas
Frem1 and
Frem2 expression
in the interfollicular regions tends to be markedly reduced
in comparison (16
,17
).
Frem2 is also expressed in a highly dynamic
pattern in the endoderm and ectoderm of the branchial arches
and in a number of important neural signalling centres including
the midline of the dorsal forebrain and midbrain/hindbrain boundary
(17
).
Grip1 is expressed in a variety of other locations, probably
reflecting its diverse role in modulating protein trafficking
(15
,32
,33
).
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Figure 2. Embryonic expression of the blebs genes. Frem1, Frem2 and Fras1 are widely expressed during embryonic development. Although Fras1 is broadly and strongly expressed in the embryonic epidermis, expression of Frem1 and Frem2 is comparatively reduced in the inter-follicular epidermis. Expression of both of these genes is restricted to site of epithelial/mesenchymal interactions including the hair follicle, whisker vibrissae, mammary glands and apical ectodermal ridge (AER) (A, C and D, Frem2) (B, Frem1). The genes are also strongly expressed in developing organs affected both in the blebs mutants and in the FS patients, including the kidney and lung (E, Frem2 expression in Lu, lung and Ki, kidney). In most cases, Frem1 expression in the mesenchyme mirrors Frem2 and Fras1 expression in the overlying epithelium.
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THE ROLE OF THE Frem AND Fras GENES IN EPIDERMAL ADHESION
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Cryptophthalmos and syndactyly are the most striking physical
features of FS and the blebs mice. We reason that they both
arise as a consequence of loss of epidermal adhesion, leading
to interrupted epidermal/mesenchymal interactions between the
eyelid epithelia or limb AER and the underlying mesenchyme.
In all the mutants, the separation between the epidermis and
the dermis occurs below the level of the lamina densa, the lowermost,
collagen IV rich component of the basement membrane (BM). Given
the established interaction between the NG2 protein and the
collagens V and VI (which also contribute to the BM), we and
others have studied the deposition of these proteins in the
blebs mutants.
Grip1 and
Fras1 mutants display defects in deposition
of these proteins and this may contribute to epidermal delamination
(12
,13
,15
); however, the same is not true in
Frem1 and
Frem2 null mice (16
,17
). Thus, the steps leading to blistering are
only partly understood.
What is perhaps most striking about all of the mutants is the ability of the epidermis to repair itself, often after suffering delamination, which is frequently sufficient to kill the embryo. This observation, and the absence of postnatal skin blistering in the blebs mice, suggests that there is a temporal developmental window when these proteins are required for epidermal adhesion, but that later in gestation, other components of the ECM can functionally compensate for their loss. The blistering defects in the blebs mice mirror the effects of loss of collagen VII, which causes dystrophic epidermolysis bullosa (DEB) in humans (34). Collagen VII contributes to the anchoring fibrils, which consolidate the interaction between the dermis and the epidermis; however, its loss results primarily in postnatal rather than in utero blistering (34). In addition, collagen VII deposition is unaffected in Fras1 mutants and is only partly defective in mice lacking Grip1, suggesting that epidermal separation in DEB is distinct from that of FS or the blebs mice.
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ORGANOGENESIS
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Renal defects are a hallmark of FS and all of the ‘bleb’
alleles identified so far. The agenesis apparent in these models
is triggered very early during the development of the kidney,
with reduced and apoptotic mesenchymal condensations surrounding
the ureteric bud as early as E11.5 (13
,15
).
Frem2 and
Fras1 are both strongly expressed in the nephric epithelium, especially
in the tips of the buds, whereas
Frem1 is expressed at lower
levels in the stroma, a pattern which continues as the ureteric
tree branches and differentiates (16
,17
). Cystic disease in
the blebs mice has been best studied in
Frem2 and
Fras1 mutants.
Animals homozygous for mutations in either or both of these
genes develop cortical renal cysts by 12 weeks of age (17
).
The hyper-proliferative and hyper-apoptotic cysts express markers
of both the collecting ducts and the thick ascending loops of
Henle. In wild-type mice,
Frem2 is expressed strongly in adult
kidneys in the collecting ducts, proximal convoluted tubules
and arterioles which, in combination with the development of
renal cysts in the mutant animals, suggest that the protein
is required for the maintenance of the differentiated state
of the mature renal epithelia.
Fras1 also has a role in regulating
the normal lobular development of the lung and of the vascular
tissue in the terminal air sacs (35
).
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FUNCTIONAL ANALYSIS
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Given their multidomain structure, it is highly likely that
the Frem and Fras proteins interact with many different components
of the ECM and that some of these interactions are required
for the normal epidermal adhesion (Fig.
3). Their similarity
to NG2 and the observation of some defects in collagen deposition
in the BM indicate that one of these interactions is with collagens
V and VI, although mice null for these proteins do not display
a ‘bleb’ like phenotype (36
,37
). Given the complementary
expression pattern of
Frem1 and
Frem2/
Fras1 and the similarity
of the CSPG domains to cadherin, we have proposed that the proteins
may form homodimeric or heterodimeric associations. Engagement
of ligands to the ectodomain of NG2 induces cell spreading and
alterations in the actin cytoskeletion mediated by Rac1, cdc42,
Ack1 and p130cas (38
,39
), raising the possibility of signalling
via engagement of Fras1/Frem2. A recent study by Kiyozumi
et al. (40
) has also demonstrated that Frem1 is capable of mediating
cellular adhesion
in vitro through interactions with
v and
8
containing integrins. Mice null for these integrin subunits
display no obvious skin defects, which means that it is unlikely
to be the sole mechanism by which Frem1 mediates epidermal adhesion.
However, mice lacking the
8 subunit are characterized by severe
renal dysgenesis (41
), suggesting that its interaction with
Frem1 might be of functional importance.
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FUTURE DIRECTIONS AND OUTSTANDING QUESTIONS
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The cloning of the blebs mutants and the identification of FS
mutations have finally proven a genetic association first proposed
some 17 years ago. This has given us a new insight into the
early events in epidermal differentiation and BM assembly and
nephrogenesis. The proteins involved are largely uncharacterized,
and their interactions with components of the ECM are only just
beginning to be understood. Various aspects of human disease
are also puzzling. Why are the majority of mutations found in
Fras1 when the phenotypes of the different blebs mutants are
so similar? Does loss of Frem1 and Grip1 in humans lead to more
severe phenotypes, and if this is the case, are we aware of
the full influence of these proteins on early development? Although
the large size and complex domain organization of these proteins
will make dissecting their function challenging, knowledge of
the human and mouse phenotypes which result from their loss
is already providing avenues by which to pursue these studies.
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ACKNOWLEDGEMENTS
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We would like to thank the Wellcome Trust and Cancer Research
UK for support. I.S. was funded by a Wellcome Trust Travelling
Research Fellowship. We would also like to thank the families
and clinicians who have helped support our work.
Conflict of Interest statement. None declared.
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FRASER SYNDROME