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 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.

Microfibril (non-fibrillin) associated proteins

MAGP-1 MAGP-2 MFAP3-4 AAAP-40 Fibulin BMP Proteoglycans (perlecan, decorin,

versican)

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)

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

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).

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.

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

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.

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

Genetics TGFβR1 and 2 are associated with

severe vascular manifestations• Aneurysms at early age and distant

aneurysms

Other related disorders MASS phenotype and familial mitral

valve prolapse: Myopia, minimal aortic dilation, subtle skeletal changes, skin stria.

Familial tall stature Contractural arachnodactyly

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

Clinical manifestations (cont) Skeletal system

• Pectus excavatum/carinatum• Hypermobility• Scoliosis• Reduced upper/lower extremity ratios• Pes planus• Long tapering fingers and toes• Dolichocephaly

Clinical manifestations (cont) Ocular

• Ectopia lentis• Flat cornea• Hypoplastic iris• Increased axial length of ocular globe

Clinical manifestations (cont) Integumentary system:

• Skin striae.• Hernias

Marfan Syndrome. Hemopericardium

Marfan Syndrome. Aortic tear

Marfan Syndrome. Aortic tear

Marfan Syndrome. Aortic dissection

Marfan Syndrome. “Floppy” Mitral Valve

Thanks for your attention