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The Biology of Marfan Syndrome

Paper Type: Free Essay Subject: Biology
Wordcount: 2497 words Published: 23rd Sep 2019

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The Biology of Marfan Syndrome


Marfans syndrome (MFS) is a connective tissue disorder, affecting multiple organ systems around the body, leading to a large variety of symptoms. It is an incurable disease, with symptoms commonly occurring during puberty, neonatal Marfan syndrome is an exception to this as symptoms are present at birth. The disease is caused by over a thousand different mutations, making genotype-phenotype correlations challenging. The most common symptoms include cardiovascular manifestations, skeletal systems involvement and ocular manifestations. The involvement of the aorta is the leading cause of death in MFS patients, but this manifestation can be treated with beta blockers, increasing life expectancy and quality of life. FBN1 is the causative gene of MFS, it encodes the fibrillin-1 protein meaning MFS patients have lower levels of fibrillin-1. This reduces the amount of microfibrils available in the extracellular matrix increasing the amount of transforming growth factor  signalling.


Marfans syndrome (MFS) is a connective tissue disorder caused by a mutation in the fibrillin 1 (FBN1) protein. It occurs in approximately 1 in 5000 individuals, with no correlation to either gender or race (1). The disease predominantly effects the heart, blood vessels, skeleton and ocular systems as these organs are reliant on microfibrils formed by fibrillin-1 for normal functioning. MFS is characterised by tall individuals with long limbs, fingers and toes. 75% of the time MFS is inherited as an autosomal dominant disorder (2), so one copy of the mutated gene in each cell will cause MFS, the other 25% of the time the disease is caused by a random mutation. The mutated FBN1 has phenotypic variance, making early diagnosis difficult as different patients symptoms vary extensively. Most manifestations of the disease occur during puberty; neonatal Marfans syndrome (nMFS) is an exception to this and symptoms are often present at birth, making nMFS a more serious strain of the disease (2). Diagnosis of MFS relies on a multidisciplinary team of healthcare professionals and the ghent nonsology is commonly used to determine if the patient has the disease(2).

Structure and function of fibrillin-1

Fibrillin-1 is made from the FBN1 gene, located on chromosome 15 (3). It consists of various repeated domains containing 47 Epidermal Growth Factor like domains (shown in figure 1). Each domain contains 6 cysteine residues, 43 out of the 47 domains contain a calcium binding sequence (3).


Figure 1- Representation of the varying repetitive domains in the Fibrillin-1 protein. The most prominent domain is shown to be the calcium binding EGF like domain, interspersed with many cytesine domains.  (adapted from (3))

Fibrillin-1 forms a large calcium binding glycoprotein, responsible for the formation of 10-12nm microfibrils in the extracellular matrix of connective tissue and has an anchoring function in some cells.(1) These microfibrils provide strength and flexibility to connective tissue, for example in the aortic wall they form a scaffold for the deposition of elastin, which in turn increases the durability of the aorta. The microfibrils also help control cellular signalling, as fibrillin regulates the availability of the transforming growth factor beta (TGF-β) family (3).

When functioning normally, the FBN1 gene makes fibrillin one protein, which is transported into the extracellular matrix by fibroblasts and binds to other fibrillin one molecules to form microfibrils (4) The microfibrils contain TGF-β, this protein plays a role in controlling cell growth. The microfibrils are able to control the activity of TGF-β because within the microfibrils TGF-β is inactive and when released from the microfibrils it becomes active.(4) However, as shown in figure one, in MFS sufferers there is a reduced amount of functioning microfibrils made, due to less fibrillin one being secreted from cells, leading to an excess of active TGF-β.

Figure 2 (4)- Representation of the difference in microfibrils formed in a healthy individual compared to an individual with MFS. More microfibrils are available in healthy individuals, resulting in normal levels of active TGF-β.

Figure 3- (5) Flow chart showing the main MFS manifestations. Three main body systems are affected, the ocular system, cardiovascular system and the skeletal system. All three systems are affected by the same mutation as this mutation causes a change in Fibrillin-1, which is essential for these body systems normal functioning.


Figure 3 shows how decreased fibrillin-1 levels resulting in excess TGF-β cause the variety of symptoms seen in MFS sufferers. The surplus active TGF-β represents a group of cytokines that control cell growth through, cell differentiation, cell proliferation and apoptosis (5). In MFS patients excess TGF-β can cause smooth muscle cell apoptosis(5), triggering additional weakening of the vascular walls, this results in aortic dilation and dissection. There are also increased levels of matrix metalloproteinase enzyme (as shown in figure 3), this degrades the extracellular matrix at a higher rate than normal resulting in abnormal bone growth, represented in the symptoms scoliosis and arachnodactyly (5). Ectopia lentis, is another indicator of MFS, affecting 60% of individuals with the disease (2). It is caused by weakness in connective tissue strands that hold the lens in place within the eye, displacing the lens from its normal position.

The mutation underpinning marfan syndrome

There are currently over 1300 known mutations that give arise to MFS, these mutations can occur throughout the entire FBN1 gene, explaining the variability in which the disease is expressed by different individuals (6). The only mutations regularly recorded encompass exons 24-32 which give arise to the more serious neonatal Marfans syndrome, these are generally de novo mutations (1). In classical MFS, mutations normally occur elsewhere throughout the entire gene, the most common of these involving cytesine; either deleting or inserting cytesine residues into the amino acid chain at the primary protein structure (3). Cysteine contains a sulfur side chain so makes strong covalent disulfide bonds during the formation of proteins. An alteration in this displuhide bonding pattern can give arise to the faulty fibrillin one protein as the quaternary protein structure is compromised. To highlight this cysteine mutation, a study of 196 MFS missense mutations locations were analysed, 130 of these individual’s mutations involved cytesine, in 111 cases a cysteine residue was replaced and in 19 extra cysteine was created (7). Another common mutation that causes MFS effects the calcium binding domain of the FBN1 gene (3). The calcium binding domain of the gene is highly conserved, indicating its importance in the overall functioning of the gene . A modification in this calcium binding site typically causes fibrillin to be vulnerable to proteolytic degradation (5).

However, the mutations in nMFS have much less variability, they normally occur between exons 24-32. (4)Missense mutations, deletions and exon being skipped have all been recorded, the more severe phenotypes often arise from exons being skipped. It is likely that exons being skipped effects the lateral alignment of fibrillin monomers, producing a severe interruption of microfibril formation. 95% of patients with nMFS die within the first year of life with heart failure being the leading cause of death, effecting 85% of patients(3).

Genetics of Marfans syndrome

Marfans syndrome is an autosomal dominant disorder, a child will have a 50% chance of developing the disorder if one parent has the disorder as only one copy of the gene needs to be present in the cell in order to express the disease. However, 25% of the time the disease is caused by a spontaneous mutation, this mutation typically occurs when the egg or sperm is being produced (5). The range of ways the disease can be inherited help to explain the complex nature in how the disease is expressed differently in different people. Most mutations are specific to a family with MFS, approximately only 10% of mutations are shared between different families (6). Even within the same family there is still phenotypic variance, suggesting other genes play a part in the phenotypic expression of the disease.


Diagnosis and treatment of Marfans syndrome 

Diagnosis of MFS is a problematic procedure, complicated by the difference in MFS expression in different people. A multidisciplinary team of geneticists, cardiologists, orthopaedists and ophthalmologists is used in combination to help diagnosis. Often a patient presenting with one MFS symptom will be referred onto a doctors with differing specialties to aid diagnosis. The Ghent Nosology scoring system is used, this divides diagnostic features into major and minor criteria (2). Doctors then use a scoring criteria to establish whether or not a patient has the disease. Individuals with no family history require major involvement of three organ systems whereas patients with a family history of MFS require major involvement of 2 organ systems and minor involvement of a third to be diagnosed with the disease (2).  

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Treatment for MFS has advanced rapidly in the last 30 years, before open heart surgery was a treatment option the average life expectancy was only 32 years old, it has now risen to near that of a healthy individual (4). However, there is no cure for MFS and patients require a mixture of drugs and lifelong monitoring to help them remain healthy. Reducing the risk or aortic dissection is the priority of care, beta blockers are commonly used to do this as they decrease blood pressure, lowering the force exerted on the aortic walls (8). However, promising new studies have shown that a new drug, losartan could potentially further reduce the risk of aortic dissection (9). Studies done on mouse models of MFS show that blocking angiotensin type one receptor by suppressing TGF-β with losartan resulted in reduced aortic dilation compared to mice treated with only the beta blocker and the control group. The trail was then conducted on 233 people and showed similar results, that when losatarn was used in conjunction with beta blockers aortic dilation was lower than when beta blockers were used alone(9). Losartrn shows a promising alternative to beta blockers, this is especially helpful to patents who are unable to take beta blockers. Patients are also advised to restrain from strenuous activity, so pressure on their blood vessels is kept to a minimum.  Along with care for the aorta, patients will receive regular check ups from ophthalmologists and orthopedics to make sure any eye conditions are diagnosed early and to check the spine growth and breast bone, to avoid complications involving a collapsed lung.

In conclusion, marfan syndrome is a lifelong condition, effecting many systems within the body, but with proper management and treatment individuals can maintain relatively good qualities of life. MFS exemplifies how a small mutation in the base sequence of DNA can have a profound effect on more than one organ system. The abundance of connective tissue throughout the body consequently means a minor mutation in the fibrillin one gene has devastating, entire body consequences. However, current advances in MFS drug treatment developing from mouse models could mean in the future MFS patients have a reduced risk of cardiac problems, further advancing patient’s qualities of life. Conversely, treatment of MFS still needs considerable advancements before a cure is found.


(1) Kirschner R, Hubmacher D, Iyengar G, Kaur J, Fagotto-Kaufmann C, Brömme D, et al. Classical and neonatal Marfan syndrome mutations in fibrillin-1 cause differential protease susceptibilities and protein function. 2011 16 September;Vol.286(37):23.

(2) Faivre L, Masurel-Paulet A, Collod-Béroud G, Callewaert BL, Child AH, Stheneur C, et al. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations. 2009 January;Vol.123(1):8.

 (3) Sakai LY, Keene DR, Renard M, De Backer J. FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders   2016 Oct;Vol.591(1):291.

(4) Durk Hubmacher. Microfibrils and Fibrillin  2011; Available at: https://www.researchgate.net/publication/226560820_Microfibrils_and_Fibrillin. Accessed Aug, 2018.

(5) Mohammad Naderan. Cure Hunter to Treat Marfan Syndrome; Introducing New Remedies to Target Transforming Growth Factor-Beta (TGF-β). The Marfan Foundation 2012 Jan.

(6) Christian J.A Ramachandra, Ashish Mehata, Kenneth Wei Qiang Guo, Phillp Wong, Ju Le Tan, Winston Shim. Molecular pathogenesis of Marfan syndrome. 2015 May;Vol.187:591.

(7) Kieran T. Melody, Lyle J. Freeman, Clair Baldock, Thomas A. Jowitt, Veronique Siegler, Bertrand D. E. Raynal, Stuart A. Chain, Tim J. WessC. Adrain Shuttleworth, Cay M. Kielty. Marfan Syndrome-causing Mutations in Fibrillin-1 Result in Gross Morphological Alterations and Highlight the Structural Importance of the Second Hybrid Domain. JBC Journal of Biological Chemistry 2006 Aug.

(8) Yaxin.Lu Richmond.Jeremy Murat.Kekic Jianlin.Yin Brett D.Hambly. Marfan Syndrome Mutations Predominantly Alter Fibrillin Domain Folding. 2012 Jan.

(9) Bowen JM, Connolly HM. Of Marfan’s syndrome, mice, and medications. New England Journal of Medicine 2014;Vol.371 (22):2129.


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