Marfan's Syndrome and Related Disorders — More Tightly Connected Than We Thought
http://www.100md.com
《新英格兰医药杂志》
Reviewing the entry on Marfan's syndrome in my medical school–era edition of Harrison's Principles of Internal Medicine, circa 1980, reminded me anew of the transformative potential of molecular medicine. In describing this striking genetic disorder, the textbook stated that the pathogenesis of Marfan's syndrome was unknown but classified it as a connective-tissue disorder, a type of disorder that "may affect any one of the numerous steps in the biosynthesis and the metabolism of or the processes by which the macromolecules are physically organized and oriented to one another."1 Fast-forward two decades, and a scientific drama involving Marfan's syndrome and related disorders is playing out. The promise of translational research is being realized with improved diagnostics and prognostication, as well as the implementation of new therapeutic approaches that are informed by an understanding of the fundamental mechanisms of disease.
The first major breakthrough came in 1991, when missense mutations in the fibrillin-1 gene (FBN1) were discovered in two unrelated patients with Marfan's syndrome.2 This finding was the culmination of biochemical studies that had identified fibrillin as an extracellular-matrix protein, specifically, a major component of microfibrils associated with elastin fibers. The research documented the presence of a fibrillin deficiency in patients with Marfan's syndrome. Formal proof came from genetic investigations linking the trait to the region of chromosome 15 that was shown to contain FBN1, which in patients with Marfan's syndrome harbored mutations.
Although exciting, these events left intact the basic paradigm of disease: that FBN1 mutations resulted in the production of abnormal fibrillin protein that, when incorporated into microfibrils along with normal fibrillin, resulted in structurally inferior connective tissue. This adverse effect of mutant proteins on normal ones, which geneticists term "dominant negative," appeared to readily explain many of the cardinal features of Marfan's syndrome, including cardiovascular abnormalities (aortic aneurysms and mitral-valve prolapse), ophthalmologic abnormalities (dislocation of the lens), and skeletal abnormalities (joint laxity). This explanation was reinforced by the contemporaneous discovery of a second fibrillin gene, FBN2, which was associated with a related connective-tissue disorder: congenital contractural arachnodactyly (also known as Beals' syndrome).3
Interested in a richer understanding of the adverse effects of mutant fibrillins on connective-tissue homeostasis, and with the faint hope of developing better treatment, research groups developed animal models of Marfan's syndrome.4,5,6 The introduction of mutations into the mouse fibrillin-1 gene, Fbn1, recapitulated the disorder. Emphysematous changes in the lungs, a feature observed in some patients with Marfan's syndrome, were present in the affected mice. Expecting to find histologic evidence of breakdown due to repeated stretching of the connective tissue, Dietz and colleagues instead made a remarkable observation — there was abnormal septation of the distal alveoli in newborn mice pups that was more consistent with a developmental defect than indicative of breakdown.7
Next came a fascinating insight that appeared to explain the developmental perturbation of lung septation. Sakai and colleagues had observed that fibrillin was homologous with the family of latent transforming growth factor (TGF-) binding proteins (LTBPs), which serve to hold TGF- in an inactive complex in various tissues, including the extracellular matrix. The researchers showed that fibrillin can bind TGF- and LTBP (Figure 1).8,9,10 Noting this, the Dietz group hypothesized that abnormal fibrillin, or reduced levels of fibrillin, in connective tissue might result in an excess of active TGF-.7 They found support for this hypothesis and, even more exciting, found that blocking TGF- with neutralizing antibodies led to the normalization of lung development in affected mice.
Figure 1. Two Possible Models for the Interaction between TGF- and the Extracellular Matrix.
Small latent complexes containing TGF- bind LTBPs intracellularly to form large latent complexes that are then secreted into the extracellular space, where they can bind the fibrillin in microfibrils. Alternatively, small latent complexes might bind fibrillin directly and become incorporated into the extracellular matrix. However latent complexes are attached to microfibrils, TGF- becomes active through its release by proteases and then binds to receptor complexes at the cell surface.
Having shown that the pathogenesis of lung disease in Marfan's syndrome derives from an excess of TGF- activity, the next set of experiments addressed whether mitral-valve prolapse and aortic-root aneurysm might have similar causes. The use of TGF-–neutralizing antibodies prevented myxomatous changes in the mitral valve and aortic aneurysms in mice with Marfan's syndrome.11,12 Since administering neutralizing antibodies in patients would not be practical, the Dietz group and colleagues performed a trial using the angiotensin II type 1–receptor antagonist losartan, which antagonizes TGF-. They gave losartan to mice with abnormal fibrillin, starting at seven weeks of age, when aortic dilatation had already developed.11 Remarkable therapeutic efficacy was evident after six months: the mice had no further aortic dilatation and had an absence of elastin fragmentation in the aortic wall, a histologic hallmark of Marfan's syndrome. A beta-blocker, currently the treatment of choice for Marfan's syndrome, was also effective — though not as effective as losartan.
In addition to the biologic work connecting excessive TGF- activity to the pathogenesis of Marfan's syndrome, there is compelling genetic evidence. Missense mutations in TGFBR2, which encodes TGF- receptor 2 (Figure 1), have been found in patients who have a form of Marfan's syndrome, as well as in some patients with familial thoracic aortic aneurysm and dissection.13,14 In 2005, with their colleagues, Loeys and Dietz described a new autosomal dominant syndrome, which now bears their names.15 The phenotype of Loeys–Dietz syndrome overlaps with that of Marfan's syndrome (aortic aneurysm, arachnodactyly, dural ectasia), but it also includes distinctive features such as hypertelorism, craniosynostosis, cleft palate, bifid or broad uvula, and generalized arterial tortuosity. TGFBR1 or TGFBR2 mutations cause the Loeys–Dietz syndrome, and TGF- activity was found to be increased in the aorta of one affected person.
In this issue of the Journal, Loeys et al. have characterized a much larger cohort of patients with TGFBR1 or TGFBR2 mutations.16 Some had the Loeys–Dietz syndrome, but others had a phenotype resembling that of patients with vascular Ehlers–Danlos syndrome. One principal finding was that aortic dissections tend to occur at smaller aortic-root diameters in patients with TGFBR1 or TGFBR2 mutations than in those with Marfan's syndrome. The other was that patients with the Loeys–Dietz syndrome had worse survival, but better outcomes after aortic surgery, than did patients with vascular Ehlers–Danlos syndrome caused by defects in type III collagen. Aside from reinforcing the role of TGF- in aortic disease, these correlations between genotype and phenotype provide a powerful clinical rationale for the proper diagnosis.
Taken together, the genetic findings from this study and those from studies involving mouse models of fibrillinopathies show that critical portions of the Marfan's syndrome phenotype — including the cardiovascular involvement that determines the life expectancy of patients with this disorder — result from abnormal TGF- signaling. They also show that the reduction of TGF- activity with the use of pharmacologic agents significantly improves outcomes. For the aspects of the phenotype related to the heart and lung that have been studied so far (and possibly to other affected organ systems), the classic paradigm of Marfan's syndrome as a connective-tissue disorder involving mutant fibrillin with dominant negative effects has been upended. In retrospect, we should have known there was more to the pathogenesis of Marfan's syndrome than we thought, since certain aspects of the phenotype (such as overgrowth of long bones) were never well explained.
Where is this field headed? A vital next step is to determine whether an angiotensin II type 1–receptor antagonist will be as efficacious in people with Marfan's syndrome as it was in mice with mutant fibrillin-1. The National Institutes of Health is sponsoring a clinical trial that will compare losartan with beta-blocker therapy in children and young adults with Marfan's syndrome and aortic aneurysm. If losartan is shown to be efficacious, it could be attempted as a treatment for patients with TGFBR1 or TGFBR2 mutations, as well as for those with congenital contractural arachnodactyly. It might also be worth considering the role of TGF- signaling in collagenopathies such as vascular Ehlers–Danlos syndrome. Finally, there is a tantalizing hint that excessive TGF- activity may be relevant to the pathogenesis of arterial disease in the context of dysregulated glucose metabolism.17 If this is confirmed, anti–TGF- therapeutic agents might have a far larger role in the treatment of acquired vascular diseases, such as the angiopathy associated with diabetes mellitus.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Center for Molecular Cardiology, Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, New York.
References
Fialkow PJ. Disorders of connective tissue. In: Isselbacher KJ, Adams RD, Braunwald E, Petersdorf RG, Wilson JD, eds. Harrison's principles of internal medicine. 9th ed. New York: McGraw-Hill, 1980:530-6.
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-339.
Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991;352:330-334.
Pereira L, Andrikopoulos K, Tian J, et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 1997;17:218-222.
Pereira L, Lee SY, Gayraud B, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A 1999;96:3819-3823.
Judge DP, Biery NJ, Keene DR, et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 2004;114:172-181.
Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003;33:407-411.
Maslen CL, Corson GM, Maddox BK, Glanville RW, Sakai LY. Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991;352:334-337.
Gregory KE, Ono RN, Charbonneau NL, et al. The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix. J Biol Chem 2005;280:27970-27980.
Isogai Z, Ono RN, Ushiro S, et al. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 2003;278:2750-2757.
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121.
Ng CM, Cheng A, Myers LA, et al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 2004;114:1586-1592.
Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 2004;36:855-860.
Pannu H, Fadulu VT, Chang J, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 2005;112:513-520.
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-281.
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF- receptor. N Engl J Med 2006;355:788-798.
Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 2006;38:452-457.(Bruce D. Gelb, M.D.)
The first major breakthrough came in 1991, when missense mutations in the fibrillin-1 gene (FBN1) were discovered in two unrelated patients with Marfan's syndrome.2 This finding was the culmination of biochemical studies that had identified fibrillin as an extracellular-matrix protein, specifically, a major component of microfibrils associated with elastin fibers. The research documented the presence of a fibrillin deficiency in patients with Marfan's syndrome. Formal proof came from genetic investigations linking the trait to the region of chromosome 15 that was shown to contain FBN1, which in patients with Marfan's syndrome harbored mutations.
Although exciting, these events left intact the basic paradigm of disease: that FBN1 mutations resulted in the production of abnormal fibrillin protein that, when incorporated into microfibrils along with normal fibrillin, resulted in structurally inferior connective tissue. This adverse effect of mutant proteins on normal ones, which geneticists term "dominant negative," appeared to readily explain many of the cardinal features of Marfan's syndrome, including cardiovascular abnormalities (aortic aneurysms and mitral-valve prolapse), ophthalmologic abnormalities (dislocation of the lens), and skeletal abnormalities (joint laxity). This explanation was reinforced by the contemporaneous discovery of a second fibrillin gene, FBN2, which was associated with a related connective-tissue disorder: congenital contractural arachnodactyly (also known as Beals' syndrome).3
Interested in a richer understanding of the adverse effects of mutant fibrillins on connective-tissue homeostasis, and with the faint hope of developing better treatment, research groups developed animal models of Marfan's syndrome.4,5,6 The introduction of mutations into the mouse fibrillin-1 gene, Fbn1, recapitulated the disorder. Emphysematous changes in the lungs, a feature observed in some patients with Marfan's syndrome, were present in the affected mice. Expecting to find histologic evidence of breakdown due to repeated stretching of the connective tissue, Dietz and colleagues instead made a remarkable observation — there was abnormal septation of the distal alveoli in newborn mice pups that was more consistent with a developmental defect than indicative of breakdown.7
Next came a fascinating insight that appeared to explain the developmental perturbation of lung septation. Sakai and colleagues had observed that fibrillin was homologous with the family of latent transforming growth factor (TGF-) binding proteins (LTBPs), which serve to hold TGF- in an inactive complex in various tissues, including the extracellular matrix. The researchers showed that fibrillin can bind TGF- and LTBP (Figure 1).8,9,10 Noting this, the Dietz group hypothesized that abnormal fibrillin, or reduced levels of fibrillin, in connective tissue might result in an excess of active TGF-.7 They found support for this hypothesis and, even more exciting, found that blocking TGF- with neutralizing antibodies led to the normalization of lung development in affected mice.
Figure 1. Two Possible Models for the Interaction between TGF- and the Extracellular Matrix.
Small latent complexes containing TGF- bind LTBPs intracellularly to form large latent complexes that are then secreted into the extracellular space, where they can bind the fibrillin in microfibrils. Alternatively, small latent complexes might bind fibrillin directly and become incorporated into the extracellular matrix. However latent complexes are attached to microfibrils, TGF- becomes active through its release by proteases and then binds to receptor complexes at the cell surface.
Having shown that the pathogenesis of lung disease in Marfan's syndrome derives from an excess of TGF- activity, the next set of experiments addressed whether mitral-valve prolapse and aortic-root aneurysm might have similar causes. The use of TGF-–neutralizing antibodies prevented myxomatous changes in the mitral valve and aortic aneurysms in mice with Marfan's syndrome.11,12 Since administering neutralizing antibodies in patients would not be practical, the Dietz group and colleagues performed a trial using the angiotensin II type 1–receptor antagonist losartan, which antagonizes TGF-. They gave losartan to mice with abnormal fibrillin, starting at seven weeks of age, when aortic dilatation had already developed.11 Remarkable therapeutic efficacy was evident after six months: the mice had no further aortic dilatation and had an absence of elastin fragmentation in the aortic wall, a histologic hallmark of Marfan's syndrome. A beta-blocker, currently the treatment of choice for Marfan's syndrome, was also effective — though not as effective as losartan.
In addition to the biologic work connecting excessive TGF- activity to the pathogenesis of Marfan's syndrome, there is compelling genetic evidence. Missense mutations in TGFBR2, which encodes TGF- receptor 2 (Figure 1), have been found in patients who have a form of Marfan's syndrome, as well as in some patients with familial thoracic aortic aneurysm and dissection.13,14 In 2005, with their colleagues, Loeys and Dietz described a new autosomal dominant syndrome, which now bears their names.15 The phenotype of Loeys–Dietz syndrome overlaps with that of Marfan's syndrome (aortic aneurysm, arachnodactyly, dural ectasia), but it also includes distinctive features such as hypertelorism, craniosynostosis, cleft palate, bifid or broad uvula, and generalized arterial tortuosity. TGFBR1 or TGFBR2 mutations cause the Loeys–Dietz syndrome, and TGF- activity was found to be increased in the aorta of one affected person.
In this issue of the Journal, Loeys et al. have characterized a much larger cohort of patients with TGFBR1 or TGFBR2 mutations.16 Some had the Loeys–Dietz syndrome, but others had a phenotype resembling that of patients with vascular Ehlers–Danlos syndrome. One principal finding was that aortic dissections tend to occur at smaller aortic-root diameters in patients with TGFBR1 or TGFBR2 mutations than in those with Marfan's syndrome. The other was that patients with the Loeys–Dietz syndrome had worse survival, but better outcomes after aortic surgery, than did patients with vascular Ehlers–Danlos syndrome caused by defects in type III collagen. Aside from reinforcing the role of TGF- in aortic disease, these correlations between genotype and phenotype provide a powerful clinical rationale for the proper diagnosis.
Taken together, the genetic findings from this study and those from studies involving mouse models of fibrillinopathies show that critical portions of the Marfan's syndrome phenotype — including the cardiovascular involvement that determines the life expectancy of patients with this disorder — result from abnormal TGF- signaling. They also show that the reduction of TGF- activity with the use of pharmacologic agents significantly improves outcomes. For the aspects of the phenotype related to the heart and lung that have been studied so far (and possibly to other affected organ systems), the classic paradigm of Marfan's syndrome as a connective-tissue disorder involving mutant fibrillin with dominant negative effects has been upended. In retrospect, we should have known there was more to the pathogenesis of Marfan's syndrome than we thought, since certain aspects of the phenotype (such as overgrowth of long bones) were never well explained.
Where is this field headed? A vital next step is to determine whether an angiotensin II type 1–receptor antagonist will be as efficacious in people with Marfan's syndrome as it was in mice with mutant fibrillin-1. The National Institutes of Health is sponsoring a clinical trial that will compare losartan with beta-blocker therapy in children and young adults with Marfan's syndrome and aortic aneurysm. If losartan is shown to be efficacious, it could be attempted as a treatment for patients with TGFBR1 or TGFBR2 mutations, as well as for those with congenital contractural arachnodactyly. It might also be worth considering the role of TGF- signaling in collagenopathies such as vascular Ehlers–Danlos syndrome. Finally, there is a tantalizing hint that excessive TGF- activity may be relevant to the pathogenesis of arterial disease in the context of dysregulated glucose metabolism.17 If this is confirmed, anti–TGF- therapeutic agents might have a far larger role in the treatment of acquired vascular diseases, such as the angiopathy associated with diabetes mellitus.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Center for Molecular Cardiology, Departments of Pediatrics and Human Genetics, Mount Sinai School of Medicine, New York.
References
Fialkow PJ. Disorders of connective tissue. In: Isselbacher KJ, Adams RD, Braunwald E, Petersdorf RG, Wilson JD, eds. Harrison's principles of internal medicine. 9th ed. New York: McGraw-Hill, 1980:530-6.
Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-339.
Lee B, Godfrey M, Vitale E, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991;352:330-334.
Pereira L, Andrikopoulos K, Tian J, et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 1997;17:218-222.
Pereira L, Lee SY, Gayraud B, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci U S A 1999;96:3819-3823.
Judge DP, Biery NJ, Keene DR, et al. Evidence for a critical contribution of haploinsufficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 2004;114:172-181.
Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003;33:407-411.
Maslen CL, Corson GM, Maddox BK, Glanville RW, Sakai LY. Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991;352:334-337.
Gregory KE, Ono RN, Charbonneau NL, et al. The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix. J Biol Chem 2005;280:27970-27980.
Isogai Z, Ono RN, Ushiro S, et al. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J Biol Chem 2003;278:2750-2757.
Habashi JP, Judge DP, Holm TM, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-121.
Ng CM, Cheng A, Myers LA, et al. TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 2004;114:1586-1592.
Mizuguchi T, Collod-Beroud G, Akiyama T, et al. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 2004;36:855-860.
Pannu H, Fadulu VT, Chang J, et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 2005;112:513-520.
Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 2005;37:275-281.
Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF- receptor. N Engl J Med 2006;355:788-798.
Coucke PJ, Willaert A, Wessels MW, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet 2006;38:452-457.(Bruce D. Gelb, M.D.)