Download Marfan syndrome: from molecular pathogenesis to clinical treatment

Marfan syndrome: from molecular pathogenesis to clinical
treatment
Francesco Ramirez and Harry C Dietz
Marfan syndrome is a connective tissue disorder with ocular,
musculoskeletal and cardiovascular manifestations that are
caused by mutations in fibrillin-1, the major constituent of
extracellular microfibrils. Mouse models of Marfan syndrome
have revealed that fibrillin-1 mutations perturb local TGFb
signaling, in addition to impairing tissue integrity. This
discovery has led to the identification of a new syndrome with
overlapping Marfan syndrome-like manifestations that is
caused by mutations in TGFb receptor types I and II. It has also
prompted the idea that TGFb antagonism will be a productive
treatment strategy in Marfan syndrome and perhaps in other
related disorders. More generally, these studies have
established that Marfan syndrome is part of a group of
developmental disorders with broad and complex effects on
morphogenesis, homeostasis and organ function.
Addresses
Institute of Genetic Medicine, Howard Hughes Medical Institute,
Johns Hopkins University, School of Medicine, BRB 539,
733 North Broadway, Baltimore, MD 21205, USA
Corresponding author: Dietz, Harry C ([email protected])
Current Opinion in Genetics & Development 2007, 17:252–258
This review comes from a themed issue on
Genetics of disease
Edited by Robert Nussbaum and Leena Peltonen
Available online 27th April 2007
0959-437X/$ – see front matter
# 2007 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.gde.2007.04.006
Introduction
Marfan syndrome (Online Mendelian Inheritance in Man
[OMIM] 154700) is a systemic disorder caused by
mutations in the extracellular matrix protein fibrillin-1.
First described by Antoine-Bernard Marfan in an 1896
case report of a young girl with unusual musculoskeletal
features [1], Marfan syndrome occupies a special place in
the history of medicine and science owing to the number
of seminal discoveries and conceptual breakthroughs that
have been associated with this disorder. A 50-year-long
analysis of the clinical and genetic features of Marfan
syndrome ultimately led Victor McKusick to delineate it
as the founding member of a larger group of congenital
conditions that he defined as the heritable disorders of the
connective tissue, and which he predicted to be the result
of structural or metabolic dysfunctions of extracellular
matrix proteins [2]. The demonstration in 1991 that
Current Opinion in Genetics & Development 2007, 17:252–258
mutations in the fibrillin-1 gene (FBN1) cause Marfan
syndrome confirmed McKusick’s prediction, and in
addition represented an early successful example of the
discovery of a disease-causing gene based on the convergence of genetic linkage studies and the candidate gene
approach [3]. Fifteen years later, the unexpected finding
that increased transforming growth factor beta (TGFb)
signaling is part of the molecular pathogenesis of
Fbn1-deficient mice has paved the way to a new drugbased strategy against the life-threatening manifestations
of Marfan syndrome [4,5]. This review highlights the
most exciting developments in the past two years of
Marfan syndrome research and discusses their impact
on the clinical management of this and related conditions,
including more common and non-syndromic presentations of Marfan syndrome.
Clinical manifestations and differential
diagnosis
The phenotype of Marfan syndrome typically involves
manifestations in the cardiovascular, skeletal and ocular
systems; additionally, the skin, integument, lung, muscle,
adipose tissue and dura can also be affected (Table 1)
[6]. Inherited as an autosomal dominant trait, Marfan
syndrome has an estimated incidence of 2–3 per 10 000
individuals. Approximately 25% of cases are caused by de
novo mutations. The disease has no ethnic or gender
predilection and shows high penetrance but marked
inter- and intra-familial variability. The most striking
and immediately evident manifestation in Marfan syndrome patients often involves a disproportionate increase
in linear bone growth that causes overt malformations of
the digits, limbs and anterior chest wall. Craniofacial
abnormalities, scoliosis and joint hypermobility are common skeletal findings as well. Early and severe myopia
and dislocation of one or both lenses of the eye occur in
the majority of Marfan syndrome patients. Cardiovascular
manifestations include progressive aortic root enlargement and abnormally thick and elongated valve leaflets.
Ascending aortic aneurysm can precipitate life-threatening complications such as aortic regurgitation, dissection
or rupture. Treatment of vascular disease in Marfan
syndrome includes regular imaging to monitor aneurysm
progression, b-adrenergic blockade to slow aortic growth,
and prophylactic surgery to prevent aortic complications.
A major problem with the clinical management of cardiovascular complications in Marfan syndrome is the difficulty
to diagnose the disorder, particularly in young children,
because of extensive phenotypic variability, age-dependent onset of informative manifestations, high degree of
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Marfan syndrome: from molecular pathogenesis to clinical treatment Ramirez and Dietz 253
Table 1
Clinical features of the Marfan and Loeys-Dietz syndromes.
Marfan
syndrome
Ocular system
Early and severe myopia
Ectopia lentis
Glaucoma
Cataract
Retinal detachment
Blue sclerae
Skeletal system
Pectus deformity
Scoliosis
Dolichostenomelia
Arachnodactyly
Joint laxity
Pes planus
Cervical spine instability
Osteoporosis
Club foot deformity
Camptodactyly
Cardiovascular system
Aortic root aneurysm
Aortic root dissection
Other primary aneurysms
Other primary dissections
Arterial tortuosity
Mitral valve prolapse
Patent ductus arteriosus
Atrial septal defect
Other septal defects
Bicuspid aortic valve
Craniofacial
Long and narrow face
Down-slant of palpebral fissures
Enophthalmos
Malar hypoplasia
Micrognatia or retrognathia
High-arched palate
Craniosynostosis
Hypertelorism
Cleft palate
Bifid uvula
Hydrocephalus
Neurocognitive
Developmental delay
Cutaneous
Striae distensae
Dystrophic scars
Translucent skin
Easy bruising
Velvety skin texture
Integument
Hernia
Dural ectasia
Visceral
Splenic rupture
Bowel perforation
Uterine rupture or hemorrhage
Inflammatory bowel symptoms
+++
+++
+
+
+
+++
+++
+++
+++
++
++
+/
+
+++
+++
+/
+/
+++
+++
++
++
+++
++
+++
Loeys-Dietz
syndrome
+
++
+++
+++
+/
+++
+++
++
++
++
++
++
+++
+++
+++
+++
+++
+
++
++
+
+
+/
++
+
+++
+++
+++
++(1)
+++(1)
++(1)
+++(2)
+
+
++
++
++
+++
+++
+++
++
+++
++
++
+
+
++
+
, not associated; +/ , rare and/or subtle; +, occasionally
observed; ++, commonly observed; +++, generally observed; (1),
by definition, not observed in Loeys-Dietz syndrome type II; (2),
rare and/or subtle in Loeys-Dietz syndrome type II.
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spontaneous mutations, or clinical overlap with several
other conditions. As our understanding of the genetic
and clinical features of Marfan syndrome has evolved, so
have the clinical criteria used to identify individuals at risk.
The current diagnostic criteria, known as the Ghent Nosology, are the product of this evolving process and provide
more stringent guidelines than before to differentiate classic Marfan syndrome from a number of connective tissue
disorders that share some Marfan syndrome-like manifestations but differ in their genetic cause, repertoire of manifestations, natural history, and response to treatment [7].
Molecular genetics and pathophysiology
Fibrillin-1 and the closely related fibrillin-2 protein
(mutated in congenital contractural arachnodactyly
[CCA]; OMIM 121050] are large glycoproteins that are
primarily made of multiple repeated domains homologous to the calcium-binding epidermal growth factor
(cbEGF) module, and a distinct 8-cysteine motif
(TB/8-cys) found uniquely in the latent TGFb binding
proteins (LTBPs) (Figure 1) [8]. Fibrillin monomers
polymerize into microfibrils that incorporate or are decorated by additional proteins, in addition to associating
with elastin in the elastic fibers (Figure 1). Microfibrils
and elastic fibers give rise to morphologically discrete
architectural assemblies that fulfill the mechanical
demands of individual organ systems, such as the elastic
fibers that together with the interposed layers of vascular
muscle cells impart elasticity to the aortic wall.
Although experimental evidence and biosynthetic considerations had suggested that loss of tissue integrity is the
underlying pathophysiology in Marfan syndrome [9],
clinical observations pointed to a larger role of fibrillinrich microfibrils in organ physiology. First, the high degree
of clinical variability in the absence of informative genotype–phenotype correlations implied that modifier genes
modulate phenotypic severity in Marfan syndrome. Second, selected manifestations of Marfan syndrome, such as
bone overgrowth, craniofacial features, valve and lung
abnormalities, and muscle and fat hypoplasia, argued for
altered cell behavior during morphogenesis. These considerations were indirectly supported by biochemical evidence that fibrillin-1 can interact with, and presumably
influence, a large variety of cell surface and extracellular
proteins, including LTBPs, molecules that target latent
TGFb to the matrix [10,11]. Binding to the extracellular
matrix provides functional context to growth factors by
regulating the spatial and temporal release, as well as the
duration and intensity of productive signaling events [11].
In this view, FBN1 mutations in Marfan syndrome might
also promote promiscuous activation of TGFb with
adverse consequences to diverse cellular activities.
Fibrillin-1 regulates TGFb bioactivity
Mice homozygous for a hypomorphic in-frame deletion
(mgD) in Fbn1 that replicate the neonatal lethal form of
Current Opinion in Genetics & Development 2007, 17:252–258
254 Genetics of disease
Figure 1
Schematic representation of the fibrillin-1 protein with its main structural motifs (a) as well as the steps leading to elastic fiber and microfibril
assembly (b). Fibrillin-1 monomers contain multiple repetitive motifs including epidermal growth factor-like (EGF) motifs, some of which adhere
to the consensus for calcium binding (cbEGF); an 8-cysteine motif with homology to that found in the latent transforming growth factor-b binding
proteins (TB/8-cys) and a hybrid motif containing features of both EGF and TB/8-cys motifs (hybrid). Upon secretion, fibrillin-1 monomers
aggregate to form complex beaded structures that in turn form macro-aggregates called microfibrils. Microfibrils can occur independently of
elastin or can surround and become embedded within elastic fibers during embryogenesis.
Marfan syndrome have provided the first in vivo evidence
supporting a role for fibrillin-1 in TGFb modulation [12].
Many individuals with Marfan syndrome show chronic
obstructive lung disease and a predisposition for pneumothorax, a process that had been equated with destructive emphysema due to impaired tissue integrity [6].
However, homozygous mgD mice display widening of the
distal pre-alveolar saccules at birth, without signs of
inflammation or tissue destruction [4]. Importantly, the
mouse phenotype was correlated with elevated TGFb
activity in lung tissue, in addition to being rescued by
systemic administration of TGFb-neutralizing antibodies. These early findings raised the possibility that
a similar mechanism underlies other manifestations of
Current Opinion in Genetics & Development 2007, 17:252–258
Marfan syndrome, a prediction that has been validated
recently in different strains of Marfan syndrome-like
mice. Ng et al. [13] have associated architectural alterations in the mitral valves of mice heterozygous for a
structural mutation in fibrillin-1 (substitution of an obligatory cysteine in a cbEGF module; C1039G) with
increased cell proliferation, decreased apoptosis and
abnormally high TGFb activity. They have also been
able to prevent the mitral valve phenotype by TGFb
antagonism. Other reports have documented excess
TGFb activation and signaling in the dura of mgR/mgR
mice, which produce less than the normal amount of
wild type fibrillin-1, and in the aortic wall and skeletal
muscles of C1039G/+ mice [14,15].
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Marfan syndrome: from molecular pathogenesis to clinical treatment Ramirez and Dietz 255
Early analyses of mgR/mgR mice had indicated that
aneurysm progression in this adult lethal model of Marfan
syndrome is largely driven by secondary cellular events,
which are consistent with an unproductive effort by
resident vascular muscle cells to remodel an intrinsically
faulty but morphologically normal elastic matrix [16,17].
In temporal succession, these events include inappropriate production of matrix proteins and metalloproteinases,
elastic fiber calcification, vascular wall inflammation, intimal hyperplasia, and structural collapse of the vessel wall.
Addition of synthetic fibrillin-1 peptides or aortic extracts
from mgR/mgR mice to cell culture systems has more
recently suggested that proteolysis of fibrillin-rich microfibrils also contributes to aneurysm progression by stimulating the expression of metalloproteinases and
macrophage chemotaxis [18,19]. Judge et al. [20] have
shown that the aortic wall of C1039G/+ mice recapitulates
the same histopathology in the absence of a clinical end
point. Owing to their survival, C1039G/+ mice have been
employed to document that TGFb antagonism can effectively prevent histological signs of aneurysm progression
in this Marfan syndrome model [5]. These results
demonstrate that fibrillin-1 microfibrils serve an essential
role in aortic matrix homeostasis during extra-uterine life,
and that structural deficits in microfibrils promote abnormal activation of TGFb with deleterious consequences
on vascular muscle cell performance and tissue remodeling (Figure 2). Analysis of vascular disease in mgN/mgN
mice (which do not produce fibrillin-1) has recently
shown that dissecting aortic aneurysm in this neonatal
lethal model of Marfan syndrome is accounted for by
impaired maturation of the vessel wall, even in the
presence of normally cross-linked elastin [21].
Clinical spectrum of TGFb signaling
disorders of the connective tissue
The discovery that perturbed TGFb signaling contributes to Marfan syndrome pathogenesis predicted that
conditions that display Marfan syndrome-like manifestations might be caused by mutations in different components of the TGFb signaling network (regulators or
transducers). Loeys-Dietz syndrome (OMIM 609192) is
an illustrative example of this prediction [22]. LoeysDietz syndrome is an autosomal dominant disorder with
both unique and Marfan syndrome-like manifestations,
such as aortic root aneurysm, aneurysms and dissections
throughout the arterial tree, and generalized arterial tortuosity (Table 1). Loeys-Dietz syndrome is caused by
heterozygous substitution of evolutionarily conserved
obligatory residues in the kinase domains of the type I
or II TGFb receptor (TbR-I or TbR-II), which in
theory should attenuate TGFb signaling. Contrary to this
Figure 2
Model of normal regulation of TGFb by microfibrils and perturbations associated with microfibrillar deficiency in Marfan syndrome. Extracellular
microfibrils normally bind the large latent complex of TGFb, composed of the mature cytokine (TGFb), latency-associated peptide (LAP) and
one of three latent transforming growth factor-b binding proteins (LTBPs). This interaction is proposed to suppress the release of free and active
TGFb (TGFb activation). In the absence of a sufficient quotient of microfibrils (e.g. Marfan syndrome), failure of matrix sequestration of the large
latent complex leads to promiscuous activation of TGFb (lightening bolt). Free and active TGFb (star burst) interacts with its cell surface receptor,
culminating in phosphorylation (P) of the receptor-activated smad proteins (R-Smads 2 and 3), which then bind to Smad4 and translocate
from the cytoplasm to the nucleus, where, in combination with transcription factors (TFs), they mediate TGFb-induced transcriptional responses.
Genes downstream of TGFb induce phenotypic consequences in Marfan syndrome including developmental emphysema, myxomatous
changes of the mitral valve and mitral valve prolapse, aortic aneurysm formation and skeletal muscle myopathy. Losartan is believed to rescue
these phenotypes by decreasing the expression of TGFb, by decreasing expression of TGFb receptor or by decreasing the expression of
activators of TGFb such as thrombospondin-1.
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Current Opinion in Genetics & Development 2007, 17:252–258
256 Genetics of disease
prediction and an earlier report [23], the vessel wall of
Loeys-Dietz syndrome patients has been found to exhibit
increased TGFb signaling, and cells from these patients
have been shown to maintain TGFb responsiveness
[22].
The paradoxical findings in Loeys-Dietz syndrome
suggest that heterozygous TGFBR mutations either trigger unproductive compensatory events or have themselves gain-of-function properties. It also seems
possible that some phenotypic manifestations of LoeysDietz syndrome reflect blunted TGFb responsiveness.
This might vary in a context-specified manner. For
example, one could imagine that transient but high-level
bursts of TGFb, as might be expected during temporally
constrained developmental events, might exhaust the
capacity to propagate signal in patients with a half-normal
quotient of functional receptors. By contrast, this quotient
might be capable of handling the more subtle level of
TGFb associated with tissue homeostasis, but the chronicity of such near-threshold signaling might predispose to
altered activity of signal transducers or regulators, culminating in paradoxically enhanced signaling. Fibrillin-1
deficiency might also have dual effects on TGFb activity,
because microfibrils appear to act as both positive regulators by optimizing cytokine concentration at sites of
intended function and negative regulators by sequestering and suppressing activation of the latent TGFb complex. This mode of regulation might extend to other
TGF-b superfamily members, such as the BMPs. Indeed,
syndactyly in Fbn2 null mice has been linked genetically
with a deficiency in Bmp7 signaling, and biochemical
interaction between fibrillin-1 and the pro-domain of
Bmp-7 has recently been demonstrated [24,25]. It is
therefore plausible that complex connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome, integrate both an excess and a deficiency of
signaling by multiple cytokines.
A subset of patients with features reminiscent of the
vascular form of Ehlers-Danlos syndrome (OMIM
130050), a condition typically caused by mutations in type
III collagen, harbor heterozygous mutations in TGFRB1 or
TGFRB2 [26]. Such patients (designated Loeys-Dietz
syndrome type II) do not have the typical craniofacial
features previously associated with Loeys-Dietz syndrome
(now termed type I) but do show arterial tortuosity and
similarly aggressive vascular disease. Patients with
TGFBR mutations have also been described as having
typical Marfan syndrome or isolated thoracic aortic aneurysm [27,28]. Both groups showed atypically widespread
and/or severe vascular manifestations for these conditions.
Given that identical mutations have been observed in
individuals with Loeys-Dietz syndrome, further clinical
evaluations are needed to assess whether these mutations
cause additional features of Loeys-Dietz syndrome in
these patients; if not, such individuals might prove a
Current Opinion in Genetics & Development 2007, 17:252–258
valuable resource in the identification of genetic modifiers
that restrict phenotypic expression of TGFBR mutations.
Arterial tortuosity syndrome (OMIM 208050) is another
disorder associated with elevated TGFb activity and
characterized by vascular and skeletal manifestations that
overlap with Loeys-Dietz syndrome [29]. The underlying
defect in arterial tortuosity syndrome is loss of function of
the glucose transporter GLUT10, a defect that impairs
glucose-dependent expression of decorin, a potent extracellular inhibitor of TGFb. Finally, there are other disorders that do not fulfill the Ghent nosology but which are
occasionally caused by FBN1 mutations, such as familial
ectopia lentis, Shprintzen-Goldberg syndrome and WeillMarchesani syndrome [30–32]. It is yet to be determined
whether the majority of these patients harbor mutations
in discrete components of the TGFb signaling network.
Therapeutic applications
The demonstration that TGFb antagonism can rescue
aortic aneurysm in C1039G/+ mice prompted the idea to
test the efficacy of losartan, a widely used angiotensin II
type 1 receptor (AT1) antagonist, because of its antihypertensive properties and ability to counteract TGFb
in animal models of chronic renal disease and cardiomyopathy [33,34]. Drug administration to 2-month-old
C1039G/+ mice and 14-day-old C1039G/+ embryos for
6 and 10 months, respectively, blocked the development
of histological signs of aortic aneurysm in both cases [5].
The treatment also had a beneficial effect on alveolar
septation and muscle hypoplasia. Although the precise
mechanism whereby losartan exerts systemic TGFb
blockage remains to be elucidated, these experiments
have provided proof-of-principle that TGFb antagonism
is a general strategy against aneurysm progression in
Marfan syndrome and other disorders of the TGFb
signaling network. Similar considerations apply for the
use of losartan in the clinical management of congenital
and acquired myopathies. As in Marfan syndrome, muscle
hypoplasia is also observed in Fbn1 mutant mouse strains
and is associated with impaired muscle regeneration in
response to injury or physiologic signals for hypertrophy.
Once again, the phenotype has been shown to be
accounted for by increased TGFb signaling and to be
rescued by TGFb antagonism with either neutralizing
antibody or losartan [15]. A far-reaching finding of these
studies is that the same TGFb-dependent failure of
muscle regeneration and therapeutic response to losartan
was also seen in a dystrophin-deficient mouse model of
Duchenne muscular dystrophy, with significant improvement of muscle regeneration, architecture and function
[15].
Conclusions
Marfan syndrome research continues to yield novel
insights into the genetic etiology and pathophysiology
of a wide variety of human disorders. The new paradigm
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Marfan syndrome: from molecular pathogenesis to clinical treatment Ramirez and Dietz 257
that matrix sequestration crucially regulates the local
activation of latent TGFb has already had several important benefits. First, the TGFb signaling pathway is now
considered an attractive target to counteract aneurysm
progression in Marfan syndrome using traditional
pharmacological means of therapy. Second, TGFb involvement in Marfan syndrome pathogenesis helps to conceptualize the origin of clinical variability by providing a
number of candidate modifiers that are part of the TGFb
signaling network. Third, the genes encoding regulators
and effectors of TGFb signaling have emerged as attractive candidates for the sites of mutations causing phenotypes that overlap with Marfan syndrome or Loeys-Dietz
syndrome. Lastly, the definition of Marfan syndrome has
changed from a structural disorder of the connective
tissue to a developmental abnormality with broad and
complex effects on the morphogenesis and function of
multiple organ systems. The expanding concept of the
extracellular matrix as both a structural and instructional
entity will probably have relevance to many other disorders with extreme implications for therapeutic interventions.
Acknowledgements
We thank Ms Karen Johnson for preparing the manuscript, and members
of our laboratories for their enthusiastic involvement in the work
described in this review. These studies were supported by grants from the
National Institutes of Health (AR-42044, AR-049698, AR41135), as well as
by the Howard Hughes Medical Institute, Smilow Center for Marfan
Syndrome Research, Broccoli Foundation and the National Marfan
Foundation.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
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