The mgΔlpn mouse model for Marfan syndrome recapitulates the ocular phenotypes of the disease
Rodrigo Barbosa de SouzaIsabela Gerdes GyuriczaLuara Lucena CassianoLuis Ernesto Farinha-ArcieriAna Maria Alvim LiberatoreSheila Schuindt do CarmoWaldir CaldeiraMarcio V. CruzAlberto F. RibeiroRoberto TedescoDieter P. ReinhardtRicardo Luiz SmithIvan Hong Jun KohLygia da Veiga Pereira
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Keywords:
Fibrillin
Ectopia lentis
Ciliary processes
Microfibril
To determine the distribution and structure of fibrillin microfibrils in the three fibrillin-rich lens capsule zones of subjects with the Marfan syndrome.Capsules were dissected from nine lenses extracted intracapsularly from Marfan syndrome patients. The capsules were divided and mounted flat on gelatin-coated glass slides. ABC immunoperoxidase staining with monoclonal anti-fibrillin antibody was used to visualize and localize fibrillin in these specimens. The staining patterns and microscopic structure of microfibrils were compared to those of normal controls.There were no bundles of fibrillin fibers in Zone I - a 0.75-mm wide peripheral ring of the anterior capsule that normally contains radial bunches of fibrillin fibers; instead, fine disorganized fibrillin-positive fragments were dispersed in this region. The size and shape of the fragments varied among patients. In contrast to normal lenses, there was only light staining for fibrillin in Zone II - a 1-mm wide meshwork of normally fibrillin-rich fibers that encircles the equator and serves as an insertion platform for most zonular fibers. The radial periodic bands of Zone III - a 0.1-mm wide ring on the most peripheral part of the normal posterior capsule - were identifiable in some samples, but stained only faintly for fibrillin.Fibrillin microfibrils are disrupted and fragmented in the lens capsule of patients with the Marfan syndrome. The qualitative, quantitative, and structural abnormalities of fibrillin deposition in the lens capsule of these patients support a causal relationship to lens abnormalities in this disease.
Fibrillin
Microfibril
Capsule
Ectopia lentis
Pseudoexfoliation
Lens capsule
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Ultrasound biomicroscopy
Ectopia lentis
Ciliary processes
Quadrant (abdomen)
Ciliary muscle
Ciliary arteries
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Fibrillin
Microfibril
Ectopia lentis
Arachnodactyly
Connective Tissue Disorder
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We have found abnormal fibrillin microfibrils isolated from tissues and cell cultures from two cousins with Marfan syndrome whose major clinical abnormality is bilateral ectopia lentis, but who also have skeletal involvement but no cardiovascular defects. Ultrastructural analysis of ciliary zonules showed the presence of abundant loose microfibril bundles which in many places appeared disorganised. Microfibrils isolated from ciliary zonules and vitreous were highly fragmented when examined by rotary shadowing electron microscopy. Investigation of microfibrils elaborated by patient dermal fibroblasts showed remarkable variations in periodicity and packing. The synthesis and secretion of fibrillin by these cells was confirmed electrophoretically with the identification of metabolically labelled immunoprecipitated fibrillin (M(r) 300,000) in medium and cell layer compartments. These data show that fibrillin expression is normal but that assembled microfibrils are manifestly abnormal both morphologically and functionally. The occurrence of microfibrils with variable periodicities and susceptibility to fragmentation suggests that structural weakness is probably the primary cause of lens dislocation in these patients.
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Microfibril
Ectopia lentis
Ciliary processes
Fragmentation
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Ectopia lentis
Fibrillin
Ciliary processes
Uvea
Ciliary muscle
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Abstract Elastic system fibers are composed of two distinct elements, elastin, which is an amorphous component crosslinked in the core, and microfibril, localized in the periphery of elastin. As microfibrillar proteins, fibrillins, microfibril‐associated glycoproteins (MAGPs), latent TGF‐β‐binding proteins (LTBPs), microfibril‐associated proteins (MFAPs), and fibulins are known. Fibrillin‐1 is a major microfibrillar protein and characterized by calcium binding EGF‐like (cbEGF) domain. Association between fibrillin‐1 and TGF‐β is a recent topic of this field and this interaction is known to inactivate and target TGF‐β action. FBN1 encoding fibrillin‐1 is a responsible gene for Marfan syndrome type 1 (MIM ♯154700), characterized by increased height and long limbs, ectopia lentis, and cardiovascular disorders, such as mitral valve prolapse and aortic dilation and regurgitation. Animal models suggest that the abnormal TGF‐β signaling is underlying as the pathogenesis of these conditions. Besides skeletal, ocular and cardiovascular conditions, severe periodontitis is frequently seen in affected patients. To clarify the unknown function of elastic system fibers in the periodontal ligament (PDL), PDL‐cells were isolated from a Marfan syndrome type 1 patient who was with the severe periodontitis and had a mutation in one of the cbEGF domain of fibrillin‐1. These results suggested that wild‐type fibrillin‐1 was required for the normal cell alignment and tissue architecture of PDLs. Evidences are now accumulated to suggest that fibrillin‐1 is one of the molecule involved in the interaction between cell and extracellular matrix. J. Exp. Zool. (Mol. Dev. Evol.) 312B:503–509, 2009 . © 2009 Wiley‐Liss, Inc.
Fibrillin
Microfibril
Ectopia lentis
Periodontal fiber
Periostin
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Fibrillin
Microfibril
ADAMTS
Ectopia lentis
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Objective:
To better understand the ocular manifestations of the Marfan syndrome, we investigated the distribution of fibrillin in normal human ocular tissues. Fibrillin, a microfibrillar glycoprotein component of the extracellular matrix, has been found to be the defective gene product in the Marfan syndrome.Methods:
Frozen sections from seven pairs of normal eyes were stained with mouse anti—human fibrillin antibodies using the avidin-biotin immunoperoxidase technique.Results:
In the anterior segment, the following exhibited positive staining for fibrillin: the lens capsule and zonules; connective tissues of the iris, ciliary body, ciliary processes, and conjunctiva; and the basement membrane regions of the corneal epithelium and endothelium of Schlemm's canal. Posteriorly, fibrillin localized to the lamina cribrosa, sclera, choroid, and Bruch's membrane.Conclusions:
Fibrillin is widely distributed in ocular connective tissues. The implications of defects in these tissues and the resultant ocular abnormalities in the Marfan syndrome such as ectopia lentis and glaucoma are discussed.Fibrillin
Sclera
Ectopia lentis
Choroid
IRIS (biosensor)
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Fibrillin
Microfibril
Ectopia lentis
Arachnodactyly
Connective Tissue Disorder
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Citations (3)