Editing Marfan syndrome (section)

==Pathogenesis==

[[Image:Myxomatous aortic valve.jpg|thumb|[[Micrograph]] demonstrating [[myxomatous degeneration]] of the aortic valve, a common manifestation of MFS|alt=]]
Marfan syndrome is caused by mutations in the ''FBN1'' [[gene]] on [[Chromosome 15 (human)|chromosome 15]],<ref>{{cite journal | vauthors = McKusick VA | title = The defect in Marfan syndrome | journal = Nature | volume = 352 | issue = 6333 | pages = 279–281 | date = July 1991 | pmid = 1852198 | doi = 10.1038/352279a0 | doi-access = free | bibcode = 1991Natur.352..279M }}</ref> which [[Genetics|encodes]] [[fibrillin 1]], a glycoprotein component of the extracellular matrix. Fibrillin-1 is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue, but also serves as a reservoir for growth factors.<ref name="robspath">{{cite book|title=Robbins Pathologic Basis of Disease| vauthors = Robbins SL, Cotran RS, Robbins SL, Kumar V |publisher=W.B Saunders Company|location=Philadelphia|isbn=978-0-7216-7335-6|year=1998}}</ref> Elastic fibers are found throughout the body, but are particularly abundant in the aorta, [[ligament]]s and the [[Zonule of Zinn|ciliary zonule]]s of the eye; consequently, these areas are among the worst affected.

A [[Genetically modified organism|transgenic]] mouse has been created carrying a single copy of a mutant fibrillin-1, a mutation similar to that found in the human gene known to cause MFS. This mouse strain recapitulates many of the features of the human disease and promises to provide insights into the [[pathogenesis]] of the disease. Reducing the level of normal fibrillin 1 causes a Marfan-related disease in mice.<ref name="micefib">{{cite journal | vauthors = Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, Biery NJ, Dietz HC, Sakai LY, Ramirez F | display-authors = 6 | title = Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 7 | pages = 3819–3823 | date = March 1999 | pmid = 10097121 | pmc = 22378 | doi = 10.1073/pnas.96.7.3819 | doi-access = free | bibcode = 1999PNAS...96.3819P }}</ref>

[[Transforming growth factor]] beta ([[TGF beta|TGF-β]]) plays an important role in MFS. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. The simplest model suggests reduced levels of fibrillin-1 allow TGF-β levels to rise due to inadequate sequestration. Although how elevated TGF-β levels are responsible for the specific pathology seen with the disease is not proven, an inflammatory reaction releasing proteases that slowly degrade the elastic fibers and other components of the extracellular matrix is known to occur. The importance of the TGF-β pathway was confirmed with the discovery of the similar [[Loeys–Dietz syndrome]] involving the ''TGFβR2'' gene on [[Chromosome 3 (human)|chromosome 3]], a [[receptor protein]] of TGF-β.<ref name="tgf2beta">{{cite web|url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=gene&dopt=full_report&list_uids=7048|title=TGFBR2 transforming growth factor, beta receptor II|access-date=January 11, 2007|publisher=NCBI|year=2007|author=Entrez Gene|format=Entrez gene entry|url-status=live|archive-url=https://web.archive.org/web/20070113123129/http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve|archive-date=January 13, 2007}}</ref> Marfan syndrome has often been confused with Loeys–Dietz syndrome, because of the considerable clinical overlap between the two pathologies.<ref name="loeysdietz">{{cite web|url=http://www.marfan.org/nmf/GetContentRequestHandler.do?menu_item_id=84|title=Related Disorders: Loeys–Dietz |access-date=January 11, 2007|publisher=National Marfan Foundation |archive-url = https://web.archive.org/web/20060925143304/http://www.marfan.org/nmf/GetContentRequestHandler.do?menu_item_id=84 <!-- Bot retrieved archive --> |archive-date=September 25, 2006}}</ref>

===Marfanoid–progeroid–lipodystrophy syndrome===
{{Main|Marfanoid–progeroid–lipodystrophy syndrome}}
[[Marfanoid–progeroid–lipodystrophy syndrome]] (MPL), also referred to as Marfan lipodystrophy syndrome (MFLS), is a variant of MFS in which Marfan symptoms are accompanied by features usually associated with [[neonatal progeroid syndrome]] (also referred to as Wiedemann–Rautenstrauch syndrome) in which the levels of [[white adipose tissue]] are reduced.<ref>{{cite web|url=http://www.omim.org/entry/616914|title=OMIM Entry - #616914 - MARFAN LIPODYSTROPHY SYNDROME; MFLS|website=omim.org|access-date=2016-12-06|archive-date=2018-11-30|archive-url=https://web.archive.org/web/20181130122757/http://www.omim.org/entry/616914|url-status=live}}</ref> Since 2010, evidence has been accumulating that MPL is caused by mutations near the 3'-terminus of the [[FBN1 gene|''FBN1'' gene]].<ref>{{cite journal | vauthors = Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillessen-Kaesbach G, Fahsold R, Schmidt H, Hoffmann K, Passarge E | display-authors = 6 | title = Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3' terminus of the FBN1-gene | journal = American Journal of Medical Genetics. Part A | volume = 152A | issue = 11 | pages = 2749–2755 | date = November 2010 | pmid = 20979188 | doi = 10.1002/ajmg.a.33690 | s2cid = 26408208 }}</ref><ref>{{cite journal | vauthors = Jacquinet A, Verloes A, Callewaert B, Coremans C, Coucke P, de Paepe A, Kornak U, Lebrun F, Lombet J, Piérard GE, Robinson PN, Symoens S, Van Maldergem L, Debray FG | display-authors = 6 | title = Neonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene | journal = European Journal of Medical Genetics | volume = 57 | issue = 5 | pages = 230–234 | date = April 2014 | pmid = 24613577 | doi = 10.1016/j.ejmg.2014.02.012 | url = https://biblio.ugent.be/publication/5661161/file/5661193 }}</ref> It has been shown that these people are also deficient in [[asprosin]], a gluco-regulatory protein hormone which is the C-terminal cleavage product of profibrillin. The levels of asprosin seen in these people were lower than expected for a heterozygous genotype, consistent with a [[dominant negative]] effect.<ref>{{cite journal | vauthors = Romere C, Duerrschmid C, Bournat J, Constable P, Jain M, Xia F, Saha PK, Del Solar M, Zhu B, York B, Sarkar P, Rendon DA, Gaber MW, LeMaire SA, Coselli JS, Milewicz DM, Sutton VR, Butte NF, Moore DD, Chopra AR | display-authors = 6 | title = Asprosin, a Fasting-Induced Glucogenic Protein Hormone | journal = Cell | volume = 165 | issue = 3 | pages = 566–579 | date = April 2016 | pmid = 27087445 | pmc = 4852710 | doi = 10.1016/j.cell.2016.02.063 }}</ref>