Marfan syndrome: from molecular pathogenesis to clinical treatment

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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 TGFβ 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 TGFβ receptor types I and II. It has also prompted the idea that TGFβ 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.

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 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 (TGFβ) signaling is part of the molecular pathogenesis of Fbn1-deficient mice has paved the way to a new drug-based 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.

Section snippets

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-

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 TGFβ binding proteins (LTBPs) (Figure 1) [8]. Fibrillin monomers polymerize into microfibrils that incorporate or are decorated by additional

Fibrillin-1 regulates TGFβ bioactivity

Mice homozygous for a hypomorphic in-frame deletion (mgΔ) in Fbn1 that replicate the neonatal lethal form of Marfan syndrome have provided the first in vivo evidence supporting a role for fibrillin-1 in TGFβ 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 mgΔ mice display widening of the distal

Clinical spectrum of TGFβ signaling disorders of the connective tissue

The discovery that perturbed TGFβ 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 TGFβ signaling network (regulators or transducers). Loeys-Dietz syndrome (OMIM 609192) is an illustrative example of this prediction [22••]. Loeys-Dietz syndrome is an autosomal dominant disorder with both unique and Marfan syndrome-like manifestations, such as aortic root

Therapeutic applications

The demonstration that TGFβ 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 anti-hypertensive properties and ability to counteract TGFβ 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

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 that matrix sequestration crucially regulates the local activation of latent TGFβ has already had several important benefits. First, the TGFβ signaling pathway is now considered an attractive target to counteract aneurysm progression in Marfan syndrome using traditional pharmacological means of therapy. Second, TGFβ involvement in Marfan

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

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.

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