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== Diseases caused by mutation ==

~~The~~ [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)]

Dominant mutations in the fibrillin-1 gene cause [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)] and illustrate the physiological functions of elastic fibers. Most of the thousand known '''fibrillin-1''' mutations make the protein unstable and susceptible to proteolysis. Other point mutations interfere with folding. All patients are heterozygotes.

Elastic fibers of patients with ''Marfan syndrome'' are poorly formed, accounting for most of the pathological changes. Most dangerously, weakness of elastic fibers in the aorta leads to an enlargement of the vessel, called an aneurysm, which is prone to rupture, with fatal consequences. Prophylactic replacement of the aorta with a synthetic graft and medical treatment with drugs that block adrenergic receptors allow patients a nearly normal life span. In some patients, a floppy mitral valve in the heart causes reflux of blood from the left ventricle back into the left atrium. Weak elastic fibers that suspend the lens of the eye result in dislocation of the lens and impaired vision. Weak elastic fibers result in lax joints and curvature of the spine. Most affected patients are tall, with long limbs and fingers, but the connection of these features to fibrillin is not known

It exists nearly 1 000 different mutations possible in this gene (<scene name='86/868178/Mutations/1'>possible mutations of amino acid residues associated with the MFS in the 3D model</scene>), but the most common one is a substitution of guanine by thymine at the 1538 nucleotide of the transcript. This type of mutation leads to a non-synonymous amino acid substitution '''Cys (cysteine) to Phe (phenylalanine)''' at the 528 position on the Fibrillin-1 gene. Because this cysteine is present in the calcium-binding domain's polypeptide chain, the epidermal growth factor-like domain's structure of FBN1 is modified by affecting the <scene name='86/868178/Disulfide_bridges/1'> disulfide bridge</scene>. The calcium cation cannot bind properly to the <scene name='86/868178/Ca_binding_site/1'> cb-EGF unit </scene> and therefore there is no stabilization of cb-EGF interdomain which causes defects in connective tissue. We can thus detect the Marfan syndrome by an increase of TGF-bp in the blood because the factors cannot bind to the protein due to a change in the binding domain's structure. <ref>E. Martínez-Quintana, F. Rodríguez-González, P. Garay-Sánchez, and A. Tugoresb. (2014).A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features. ''Molecular Syndormology'', volume (5), 236-240.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188161/</ref>

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@@ Line 33: / Line 33: @@
 == Diseases caused by mutation ==
-The [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)]
+Dominant mutations in the fibrillin-1 gene cause [https://www.omim.org/entry/154700?search=marfan%20syndrome&highlight=%28syndrome%7Csyndromic%29%20marfan Marfan syndrome (MFS)] and illustrate the physiological functions of elastic fibers. Most of the thousand known '''fibrillin-1''' mutations make the protein unstable and susceptible to proteolysis. Other point mutations interfere with folding. All patients are heterozygotes.
+Elastic fibers of patients with ''Marfan syndrome'' are poorly formed, accounting for most of the pathological changes. Most dangerously, weakness of elastic fibers in the aorta leads to an enlargement of the vessel, called an aneurysm, which is prone to rupture, with fatal consequences. Prophylactic replacement of the aorta with a synthetic graft and medical treatment with drugs that block adrenergic receptors allow patients a nearly normal life span. In some patients, a floppy mitral valve in the heart causes reflux of blood from the left ventricle back into the left atrium. Weak elastic fibers that suspend the lens of the eye result in dislocation of the lens and impaired vision. Weak elastic fibers result in lax joints and curvature of the spine. Most affected patients are tall, with long limbs and fingers, but the connection of these features to fibrillin is not known
 It exists nearly 1 000 different mutations possible in this gene (<scene name='86/868178/Mutations/1'>possible mutations of amino acid residues associated with the MFS in the 3D model</scene>), but the most common one is a substitution of guanine by thymine at the 1538 nucleotide of the transcript. This type of mutation leads to a non-synonymous amino acid substitution '''Cys (cysteine) to Phe (phenylalanine)''' at the 528 position on the Fibrillin-1 gene. Because this cysteine is present in the calcium-binding domain's polypeptide chain, the epidermal growth factor-like domain's structure of FBN1 is modified by affecting the <scene name='86/868178/Disulfide_bridges/1'> disulfide bridge</scene>. The calcium cation cannot bind properly to the <scene name='86/868178/Ca_binding_site/1'> cb-EGF unit </scene> and therefore there is no  stabilization of cb-EGF interdomain which causes defects in connective tissue. We can thus detect the Marfan syndrome by an increase of TGF-bp in the blood because the factors cannot bind to the protein due to a change in the binding domain's structure. <ref>E. Martínez-Quintana, F. Rodríguez-González, P. Garay-Sánchez, and A. Tugoresb. (2014).A Novel Fibrillin 1 Gene Mutation Leading to Marfan Syndrome with Minimal Cardiac Features. ''Molecular Syndormology'', volume (5), 236-240.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188161/</ref>