Editing Marfan syndrome

==Marfan syndrome==

===General background information===
*1 of 10k-20k
*1 in 5,000 **10,000 live births
*Flo Hyman
**Died of aortic rupture in the middle of a volleyball match.
http://www.kansasvolleyballassociation.org/images/flo_hyman.jpg

===Mode of inheritance===
*Autosomal Dominant Inheritance
**Because of dominant-negative effect (impaired microfibril formation)
*75% are inherited
*'''25% de novo mutations'''
*No Documented Cases of Non‐Penetrance 
*Many different missense mutations have been observed (allelic heterogeneity).
*At least one known splicing mutation: IVS63+373 mutation creates an intronic GT sequence as a new acceptor site at the 5’ terminus and results in generation of a pseudoexon.
**This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64)

===Single important gene===
*15q21.1: FBN1 gene codes for Fibrillin‐1
*Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum
*320 kDa glycoprotein, 2,871 AA
*Has 3 types of repeating modules
*'''Epidermal Growth Factor (EGF) like module'''
**'''Occurs 47 times''', 43 are Calcium binding EGF like modules
**Each has 6 cysteine residues
*TGF‐Beta Binding Protein (TGFBP) like module
**Occurs 7 times
**Each has 8 cysteine residues that form 4 disulfide bonds
*Hybrid Module
**Occurs twice

===Etiology===
*Ca2+ binding fails in EGF-like domain mutations
**Most common domain in the protein
**Ca2+ binding required for protein‐protein interactions
**Causes '''haploinsufficiency''' because half the proteins can't bind and binding between two functional proteins is required for function.


*TGF‐β Binding Protein motif mutations
**TGF‐β is important for ECM remodelling, matrix deposition, and MMP regulation.
**FBN1 normally uses it's TGF‐β binding domains to sequester TGF‐β.
**When the domain is mutated, TGF‐β is not sequestered and is therefore elevated.


*Upregulated TGF‐β may result in:
***poor ECM remodeling
***lack of matrix deposition
***decreased matrix proteins
***elevated matrix degrading enzymes (MMPs)
**http://salamano‐giovanni.blogspot.com/2009/06/collagenopathies‐and‐marfan‐syndrome.html


*Most mutations lead to less than 35% of the expected amount of fibrillin.

===Pathogenesis===

===Phenotypic information===

====Ocular Abnormalities====
*Ectopia Lentis
**Lens subluxation
**Glaucoma
*Myopia in 60%
*Retinal Detachment
*Premature Cataract Formation
*http://flyingkitten.files.wordpress.com/2008/04/eye_anatomy‐anat.jpg
*http://www.medstudents.com.br/original/revisao/marfan/marfan.htm

====Cardiovascular Abnormalites====
*Mitral valve prolapse
**Regurgitation
*Aortic Diliatation
**Enlargement
**Regurgitation
**Aneurysm
*http://www.avnrt.com/gigs/marfan1.gif

====Skeletal Abnormalities====
*Dolichostenomelia
*Pectus Excavatum
*Pectus Carinatum
*Scoliosis http://www.medicaltourismco.com/general‐surgery/pectus‐excavatum‐surgery‐abroad.
*http://www.nytimes.com/imagepages/2007/08/01/health/adam/9011Bowedchestpigeonbreast.html
*Thoracic Lordosis
*Narrow & highly arched Palate
*Joint laxity
*Arachnodactyly
*Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists)
*Steinberg (thumbs)

===Diagnosis===
*Typically diagnosed "clinically"
*Ghent criteria: Major findings in 2 systems (3 systems w/out family history) and a minor feature in a 3rd
*Systems
**Ocular
**Skeletal
**Cardiovascular
*MFS Genetic Test
**bidirectional sequence analysis of 65 exons & splice sites in the FBN1 gene
**Does not detect mutations in introns or large deletions
**99.9% accurate at detecting mutations in the 65 exons & splice sites
**70‐90% Sensitive
**Won’t find mutation ~ 10% who meet Ghent criteria
**Cost: $1800

===Treatment===
*Use multidisciplinary management
*Ocular: Ophthalmic lens correction for myopia, monitor for glaucoma & retinal detachment. Ectopic lens may need surgical intervention
*Cardiovascular: monitor mitral valves and aorta through echocardiography; β blockers
*Counseling: Advise against isometric exercises and impact sports. Pregnancy & aorta dilatation.
*Life expectancy has improved

====Losartan====
*Losartan is used for hypertension.
*It is an angiotensin II type 1 receptor antagonist; that is, it keeps angiotensin II from binding to it's type 1 receptor.
**Recall that angiotensin II causes increased activity of the triple-cotransporter at the renal tubules.
*Losartan also blocks the actions of TGF‐β.
*In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome).
*Clinical trials are ongoing.

===Recent research===

===5 important facts===
#Autosomal Dominant 75% & 25% de novo mutations
#Allelic Heterogeneity
#Mutation in the Fibrillin‐1 (FBN1 found at 15q24.1)
#Fibrillin is found in the periosteum, Connective Tissues, and suspensor ligaments.
#TGF‐β signaling is upregulated in some forms of Marfan Syndrome

===Not to be confused with===
*Mutations in FBN1 also cause:
**Neonatal Marfan syndrome
**Familial arachnodactyly
**Autosomal dominant ectopic lentis
**MASS phenotype (Marfanoid signs involving '''m'''itral valve, '''a'''orta, '''s'''keletal, and '''s'''kin).
*So, like FGFR3, there is lots of heterogeneity when one looks at the gene.
*Congenital contractural arachnodactyly (FBN2)
**Clinical presentation overlaps a bit with Marfan syndrome
**Arachnodactyly (really long, skinny fingers), pectus deformaties, scoliosis, etc.
**Some young pts have aortic root dilitation
**Caused by mutation in homologous gene to FBN1: FBN2.

===Questions and answers===
*What are the requirements for a clinical diagnosis of Marfan Syndrome?
*What signaling pathway is affected in Marfan Syndrome?