Here you can found some one-line material concerning my letter to New England about the Dietz's article on Marfan's sindrome and losartan therapy, published on the June 26, 2008 issue of The Journal. As usually all writed material is based on personal reading of scientific articles and possible are apparently unrelated each other. However they represent the course of my scientific actual knowledge concerning collagenopathies and TGFbeta related disease starting from Marfan's syndrome study.
Since more than a century ago the first professor in pediatrics in Paris, Antoine Marfan, described a young girl with long, spider-like fingers and other curious skeletal anomalies, understanding of the syndrome that now bears his name.
The Marfan syndrome is an inherited disorder of connective tissue characterized by pleiotropic manifestations of many organs, including the eyes, heart, aorta, skeleton, skin, and lung.
The cardinal ocular manifestation, ectopia lentis, was not recognized as being associated with the skeletal changes for some decades.
The cardiovascular system was found to be involved at about the same time, when severe mitral regurgitation was observed; until 1943 was identified the involvement of aortic root, and it was remained for McKusick to show in 1955 that the disease of the aorta accounted for most deaths. Life expectancy is reduced by one thrid, on average because of emergent cardiovascular complications.
By the 1930s, it was recognized that the disease was transmitted by mendelian dominant phenotype; not until 1949 the study of large pedigrees convinced skeptics that the condition was due to a single mutant gene, which needed to be present in only one copy (heterozygosity) to cause the disease.
Half a century was required to to identify the effect of the mutation of the classic triad of Marfan disease:
- ectopia lentis
- cardiovascular disease: aortic aneurism and mitral valve prolapse
- skeletal disease: joint laxity and bone overgrowth
Microfibrillar fibers make up a discrete, widely distributed, and pleiomorphic fiber system in human tissues. When visualized by electron microscopy, the fibers apper as linear bundles containing many individual microfibrils with a tubular cross-section and an average diameter of 10 to 12 nm, showing characteristic like collagen fibers type 3.
Microfibrillar fibers are considered integral components of elastic elements, but such fibers are much more widely distributed than elastin. They have been visualized by immunolocalization studies in skin, tendon, cartilage, muscle, kidney, perichondrium, periosteum, blood vessels, pleura, dura mater, and ciliary zonules of the ocular lens.
In particular McKusick has suggested that understanding the common factor in aortic media lamellar structure and the ciliary zonules causing “ectopia lentis” often present in Marfan syndrome may reveal the basic defect of this disease.
The consistent finding of stretched and occasionally broken zonular fibers in the ectopia lentis of patients with Marfan syndrome argues that these microfibrillar fibers are functionally incompetent to resist to normal stress and elongate progressively over time.
The progressive dilatation of aortic root with the fragmentation of elastic lamellae of the tunica media, the striae atrophicae in the skin, pulmonary bullae, dural ectasia as well’s seletal overgrowth can be linked to functional alteration of the lamellar structure. In particual skeltal overgrowth may be linked to diminished forces generated by periosteal and perochondrial membranes that oppose bone growth.
The absence of reticular meshworks on epidermal sections and in dermal fibroblasts culture of patients affected by Marfan syndrome shows that an alterations is present in these extracellular structures.
However other common clinical pictures can present the same alterations in fiber disposition such as in patients affected by:
- Homocystinuria: due to cystationina beta synthse defect
- Ectodermal dysplasia
- Epidermolysis bullosa-like syndrome
- Coronary artery dissection
- Paudoxantoma elasticum
- Cutis laxa: due to elastin gene mutation
The first major advance came in 1991 when missense mutations in the fibrillin-1 gene (FBN1) were discovered in two unrelated patients with the syndrome by Dietz HC et collegues. Three works on the same issue of Nature outlined the presence of such a mutation as a cause of syndromic complex. These findings were the culminations of biochemical studies that identified “fibrillin” as an extracellular matrix component and specifically such as the principal component of microfibrils associated with elastin fibers.
Whereas the work of Hollister DW in 1990 demonstrated the fibrillin deficiency in patients affected by Marfan syndrome by immunohystochemical studies, on 1994 Shores demonstrated with genetic investigations that the region of chromosome 15 was linked to marfanoid syndrome and it was shown to contain the gene coding for fibrillin.
The gene FBN1 is located on chromosome 15 q21.1, codes for fibrillin, the 350 kd protein that is the main component of extracellular microfibrils. The gene was demonstrated to be affected by mutations that resulted in a spectrum of connective tissue disorders, including but not limited to Marfan syndrome, involving structural fibrillin protein domains distributed uniformly over 10 kb FBN1 DNA sequence. So that such as in neurofibromatosis type 1 we have a relatively common dominant disorder with a high rate of new mutations, so that no easy screening test is possible. So that the demonstration of FBN1 mutation or abnormal fibrillin metabolism don’t permit or confirm the diagnosis of Marfan syndrome.
It has been estimated that the frequecy of fibrillin disorders is considerably greater than the estimated incidence of Marfan syndrome of 1 in 10.000 subjects.
Concerning Marfan syndrome four distinct phenotypically groups have been defined:
- alterations of FBN1 gene disrupting the second disulphidrile bridge in 1 of the 44 domains containing six cysteine residues shown to be related to reduced secretion of fibrillin
- nonsense mutations leading to premature termination of polypeptide synthesis shown to be related to a sinthesis of half the normal amount of fibrillin
- rapidly progressive with aortic dilatation, severe scoliosis, ectopia lentis, variable skeletal abnormalities and negligible cardiac involvement or with mitral valve prolapse with skeltal features (with absent fibrillin)
- adult type with dominant form of slowly progressive aortic aneurism without typical ocular and skeletal findings (with locally absent fibrillin)
The basic paradigm of Marfanoid habitus is that fibrillin gene 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 genetists term “dominant negative”, appeared to explain many of the cardianal feaures of Marfan syndrome.
This explanantion was reinforced by the contemporaneous discovery of a second fibrillin gene, FNB2 located on chromososme 5, which is associated with a related connective tissue disorder:
. congenital contractural arachnodactyly (Beals’ syndrome)
On late ’90 some researchers developed imbred animal models for Marfan syndrome study; the introduction of mutations into the mouse fibrillin-1 gene, FBN1, recapitulated the disorder. Interestingly lungs were more affected in mice bearing the fibrillin gene mutations showing emphysematous changes in alveolar tissue.
However Dietz HC showed that, instead of damages due to increasing breakdown due to repeated stretching of connective tissue, affected lungs presented an abnormal septation of the distal alveoli in newborn mice pups; a finding more consistent with a developmental defects than a decreased elasticyty.
On the same year, on 2003, it was demonstrated that fibrillin has an homologous structure with Latent TGF beta binding-protein (LTBPs), which serve to hold TGF beta in an inactive complex in various tissues in extracellular matrix. It was showed tha fibrillin can bind TGF beta and LTBP. Dietz HC group hypothesized that abnormal fibrillin, or reduced levels of fibrillin, in connective tissue might result in an excess of active TGF beta. They demonstrated that blocking TGF beta with neutralizing antibodies, inbred mice strains showed a normalization of lung development.
In 2005 Loeys and Dietz showed that some patients can be classified such a separated clinical entity overlapping marfan syndrome, presenting:
- aortic aneurysm
- arachnodactyly
- dural ectasia
this syndromic complex is now called Loeys-Dietz syndrome and it was due to mutations affecting genes coding for TGF beta receptor type 1 and TGF beta receptor type 2 (TGFBR1 and FGFBR2); one affected patient was found to have an increase TGF beta activity in the aortic tissue.
Interestingly studying a large cohort of patients with TGFBR1 and TGFBR2 mutations, it was demonstrated that some had the classic Loeys-Dietz syndrome with better outcome after aortic surgery, whereas others resembling patients with Ehlers-Danlos syndrome known to be linked to defects in collagen type III gene.
Taken together, the genetic findings from these studies help us to describe a group of connective tissue diseases due to inhborn error of extracellular matrix proteins with a larger incidence on populations than previously known, we can call “fibrillinopathies”.
Inhborn error of genes coding for different types of collagens give rise to “collagenopaties”:
- Osteogenesis Imperfecta: due to collagen type 1 defect
- Spondyloepyphiseo dysplasia: due to collagen type 2 defect
- Ehlers-Danlos disease: due to collagen type 3 or type 5 defect
- Mutiple Epiphyseal Dysplasia: due to collagen 9 defect
- Methapyseal Dysplasia Schmid type: due to collagen type 10 defect
- Marshall syndrome: due to collagen type 11 defect
Its’ becoming clear that collagenopathies and fibrillinopathies show sometimes the same clinical picture in affected patients; and the more common manifestation of more subtle biochemical pathways involved into signal transduction share same proteins present on extracellular matrix space for their final actions.
It’s also likely that understanding the role of these proteins present in large amount on extracellular space may explain the physical properties of tissues such as the skin and bone where connective tissue components play a relevant role.
In particular in view of recent result on marphanoid habits, involving elastin associated microfibrils in TGF beta signal transmission, it is easy to imagine a role of Bone Morphogenetic Proteins action also on mechanical transduction of physical forces applied on bone and on regulation of bone stiffness.
References
Peyritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med 1979;300:772-7.
Pyeritz RE, McKusick VA. Basic defects in the Marfan syndrome. N Engl J Med 1981;305:1011-2.
Boucek RJ, Noble NL, Gunja-Smith Z et al. The Marfan syndrome: a deficiency in chemically stable collagen-cross-links. N Engl J Med 1981;305:988-91.
Gott VL, Pyeritz RE, Magovern GJ Jr et al. Surgical treatment of aneurysms of the ascending aorta in the Marfan syndrome: results of composite-graft repair in 50 patients. N Engl J Med 1986;314:1070-4.
Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350 kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 1986;103:2499-509.
Hollister DW, Godfrey M, Sakai LY et al. Immunologic abnormalities of the microfibrillar-fiber system in the Marfan Syndrome. N Engl J Med 1990;323:152-9.
Kainulainen K, Pulkkinen L, Savolainen A et al. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990;323:935-9.
Pyeritz RE. Marfan syndrome. N Engl J Med 1990;323:987-9.
Lee B, Godfrey M, Vitale E et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991;352:330-4.
Maslen CL, Corson GM, Maddox BK et al. Partial sequence of a candidate gene for the Marfan syndrome. Nature 1991;352:334-7.
Dietz HC, Cutting GR, Pyeritz RE et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991;352:337-9.
Tsipouras P, Del Mastro R, Sarfarazi M et al. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. N Engl J Med 1992;326:905-9.
Shores J, Berger KR, Murphy EA et al. Progression of aortic dilatation and the benefit of long term beta adrenergic blockade in Marfan syndrome. N Engl J Med 1994;330:1335-41.
Francke U, Furthmayr H. Marfan’s syndrome and other disorders of fibrillin. N Engl J Med 1994;330:1384-5.
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;37:275-81.
Habashi JP, Judge DP, Holm TM et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312:117-21.
Loeys BL, Schwarze U, Holm T et al. Aneurysm syndromes caused by mutations in the TGF beta receptor. N Engl J Med 2006;355:788-98.
Gelb BD. Marfan’s syndrome and related disorders – more than tightly connected than we thought. N Engl J Med 2006;355;841-4.
Brooke BS, Habashi JP, Judge DP et al. Angiotensin II blockade and aortic-root dilatation in Marfan's syndrome. N Engl J Med 2008;358:2787-95.
Pyeritz RE. A small molecule for a large disease. N Engl J Med 2008;358:2829-31.
