diseases of the microfibril /elastic fiber system
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Diseases of the microfibril /elastic fiber system. Juan Pablo Olano M.D. Professor UTMB , 2013. Microfibril/elastic fiber system. Extracellular matrix of every organ Abundant in organs subject to mechanical stress - PowerPoint PPT PresentationTRANSCRIPT
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Diseases of the microfibril/elastic fiber
system
Juan Pablo Olano M.D.Professor
UTMB, 2013
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Microfibril/elastic fiber system Extracellular matrix of every organ Abundant in organs subject to mechanical stress Elastin: Core protein. Fibrillin directs deposition of
tropoelastin during development Microfibrils: Unbranching chains sheathing the
elastin core. Fibrillin 1 and 2. Fibrillin 3 recently described. 2 and 3 preferentially expressed in embryonic development.
Microfibrils can be present without elastin• Biomechanical anchors in basement membranes and
areas of repeated mechanical stress.
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Microfibril (non-fibrillin) associated proteins
MAGP-1 MAGP-2 MFAP3-4 AAAP-40 Fibulin BMP Proteoglycans (perlecan, decorin,
versican)
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Genetic disorders of the elastic fiber system
Elastin gene• Supravalvular aortic stenosis• Autosomal dominant cutis laxa
FBN1, TGFβR1 and TGFβ2:• Marfan’s syndrome and related disorders:
Neonatal Marfan syndrome Isolated ectopia lentis Loeys-Dietz syndrome Familial and non-syndromic thoracic aortic aneurysms and
dissections. Shprintzen-Goldberg craniosynostosis syndrome Weill-Marchesani syndrome
FBN2• Congenital contractural arachnodactyly (Beals
syndrome)
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Fibrillin 1 Multi-domain protein
• EGF-like motif with a conserved calcium binding sequence.
• Latent TGFβ binding protein motif. • Fib motif• Mutations present in all three domains.• nMFS associated with mutations in
exons 24-32. • No other correlations exist
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TGF-β Cell proliferation, differentiation Apoptosis ECM formation TGF-β1 abundant in ECM. Cysteine rich. Secreted as homodimeric proprotein
• Dimeric propeptide or Latency associated polypeptide (LAP) and growth factor
• LAP is bound to Latent TGF β binding proteins (LTBP) forming large latent complex or LLC
LTBP play an important role in folding, secreting and targeting TGF β in ECM. Also cysteine rich.
LTBP-1 interacts with fibrillin-1 (stabilizer).
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Marfan’s syndrome Autosomal dominant inherited disease that
affects the microfibril/elastic fiber system and involves several organ systems including the heart, aorta, skeleton and the eye. Clinical presentation is extremely pleiotropic.
Incidence: 2-3/10,000 population Mutations
• 1/3: Shortened molecules and decay• 2/3: Binding domains: Protein-protein
interations, calcium binding domains.
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Genetics 1991: Mutations in FBN1. High
penetrance. 25% of cases are the index case:
New mutations in the egg or sperm of parents.
>600 mutations described (most missense).
Fibrillin: 350 kDa glycoprotein. 230 kb. 65 exons. Chromosome 15q21
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Genetics MFS type 2 (MFS locus 2):
• TGFβR1 and TGFβR2• Described in 1993 in a French cohort
Caused by TGFβR2 Cardiovascular and skeletal findings. Not ocular. Difficult to differentiate from Loeys-Dietz syndrome
Loeys-Dietz syndrome• Described in 2005• Aortic aneurysms, hypertelorism, bifid uvula,
cleft palate, arterial tortuosity.• TGFβR1 and 2.
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Genetics Familial thoracic aortic aneurysms and
dissections• Described in 2005• FBN1, TGFβR1 and 2.• Overlap with Loeys-Dietz syndrome (arterial
tortuosity). Shprintzen-Goldberg syndrome
• Craniosynostosis, marfanoid skeletal abnormalities and developmental delay.
• FBN1 and TGFβR1
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Genetics TGFβR1 and 2 are associated with
severe vascular manifestations• Aneurysms at early age and distant
aneurysms
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Other related disorders MASS phenotype and familial mitral
valve prolapse: Myopia, minimal aortic dilation, subtle skeletal changes, skin stria.
Familial tall stature Contractural arachnodactyly
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Marfan Syndrome:Clinical manifestations
Cardiovascular• Dilation of ascending aorta• Dissection of aorta (30-45% deaths in
Marfan’s syndrome).• Mitral valve prolapse (more frequent
than aortic lesions).• Dilation of pulmonary artery
Pulmonary system:• Blebs, spontaneous pneumothorax
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Clinical manifestations (cont) Skeletal system
• Pectus excavatum/carinatum• Hypermobility• Scoliosis• Reduced upper/lower extremity ratios• Pes planus• Long tapering fingers and toes• Dolichocephaly
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Clinical manifestations (cont) Ocular
• Ectopia lentis• Flat cornea• Hypoplastic iris• Increased axial length of ocular globe
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Clinical manifestations (cont) Integumentary system:
• Skin striae.• Hernias
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Marfan Syndrome. Hemopericardium
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Marfan Syndrome. Aortic tear
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Marfan Syndrome. Aortic tear
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Marfan Syndrome. Aortic dissection
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Marfan Syndrome. “Floppy” Mitral Valve
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Thanks for your attention