Kendra Parr
University of New Hampshire, Manchester


Case Study:

You are a physician practicing your residency in internal medicine. One night during your clinic hours a patient is admitted to the ER after being a victim of a three car pile-up. The patient is a 19 year old female who the paramedics properly stabilized and remains unconscious with minor lacerations on her arms and legs as well as left-sided pneumothorax (collapsed lung). Soon after the nurses aspirate the free air from the thorax cavity you walk into her room. Would you like to check on your patient's stability?


To understand Marfan Syndrome it is first important to know about the tissues of the body. There are four types of animal tissues:
1.) Connective Tissue- Fibrous tissue that make up the extracellular matrix
2.) Muscle Tissue- Active contracting tissue
3.) Nervous Tissue- Neural tissue comprising the central nervous system
4.) Epithelial Tissue-Protective cover tissue

The one in which is our focus is connective tissue. What is the importance of connective tissue?

-Connective tissue acts as a framework for the other tissues for mechanical support. It acts as a transport of nutrients and metabolites as well as immunological defense (inflammation). It also aids in energy storage and haemopoisis (blood cell formation).The most common types of connective tissue are Adipose, Blood, Bone, and Cartilage. Now why is this relevant to the disorder? Let's back track a bit...

The gene FBN1 encodes for the protein FIBRILLIN-1 that is a large, extracellular matrix glycoprotein that serves as a structural component for calcium binding microfibrils. These microfibrils provide force bearing structural support in elastic and non elastic connective tissues throughout the body. (So in other words, the FBN1 gene produces many copies of the fibrillin protein that join together, with a few other necessary components, to form the structure called microfibril.

However, a mutation can occur within the sequence of the gene causing it to alter its structure and decrease it's function. DNA sequencing revealed a single letter substitution of T for G changing the amino acid glutamic acid codon at position 745 to a stop codon. (GAA-->TAA)

Bioinformatic tools to annotate the FBN1 gene:


Genomic Context describing neighboring genes
Genomic Context describing neighboring genes
Genomic Content; Chromosome: 15 Location: 15q21.1

FBN1 in MapViewer
Master map displaying gene on chromosome 15

Human Genome View:

external image map_search.cgi?taxid=9606&query=FBN1&qchr=15&strain=All&NCkey=NCID_1_1302871_130.14.22.10_9100_1292184158_1623678687&gif=1

-The FBN1 gene contains 44 tandem domains homologous to a sequence found in epidermal growth factor.
-65 exons in a 9287 base pair transcript (homologous gene in chromosome 5 called fibrillin-2)

BLASTp allows you to compare the sequence of this gene with other organisms that may have the similar regions.

FBN1 in Homo sapiens: (For entire nucleotide sequence click here)

agtatttctc tcgcgagaaa ccgctgcgcg gacgatactt gaagaggtgg ggaaaggagg gggctgcggg agccgcggca gagactgtgg gtgccacaag cggacaggag ccacagc gacagctgcg agcggagccg agcagtggct gtagcggcca cgactgggag cagccgccgc cgcctcctcg ggagtcggag ccgccgcttc tccactggca ggggccgcct gaagtgggag cagcgcctgg agaaggcggg aggagcccgg cccgggggac gggcggcggg atagcgggac cccggcggcg cggtgcgctt cagggcgcag cggcggccgc agaccgagcc ccgggcgcgg caagaggcgg cgggagccgg tggcggctcg gcatcatgcg tcgagggcgt ctgctggaga tcgccctggg atttaccgtg cttttagcgt cctacacgag ccatggggcg gacgccaatt tggaggctgg gaacgtgaag gaaaccagag ccagtcgggc caagagaaga ggcggtggag gacacgacgc gcttaaagga cccaatgtct gtggatcacg ttataatgct tactgttgcc ctggatggaa aaccttacct ggcggaaatc agtgtattgt ccccatttgc cggcattcct gtggggatgg attttgttcg aggccaaata tgtgcacttg cccatctggt cagatagctc cttcctgtgg ctccagatcc atacaacact gcaatattcg ctgtatgaat ggaggtagct gcagtgacga tcactgtcta tgccagaaag gatacatagg gactcactgt ggacaacctg tttgtgaaag tggctgtctc aatggaggaa ggtgtgtggc cccaaatcga tgtgcatgca

Species with similar sequencing regions (e-value of 0.0) include Macaca mulatta (monkey), Canis lupus familiaris (dog), and Bos taurus (cow).

Phylogeny Reconstrution of FBN1 Protein showing the evolutionary relationship among similar species.

How does the mutation of this gene cause Marfan Syndrome?

Several types of abnormalities can occur within a mutation of this gene but the main action is that it decreases fibrilin synthesis and could cause reduced secretion to the extracellular matrix. This type of outcome could damage the proper making of connective tissues throughout the body. Typical symptoms of Marfan Syndrome that is caused by this effect are:

Skeletal Problems (Faster bone growth, tall, skinny, disproportional long arms and legs,scoliosis, and a caved inward chest)
Eye Abnormalities (Myopia and lens dislocation)
Cardiac Problems (Aortic dissection which could lead to an aneurysm, mitral valve prolapse, and heart palpitations)
Nervous System Problems (Dural ectasia)
Respiratory Problems (Pneumothorax and sleep-related breathing issues)

All these symptoms are brought on by the defected connective tissue. Unfortunately, there is no diagnostic test for this disorder, however, specialist can observe the symptoms and piece together a diagnosis by:

  • information about any family members who may have the disorder or who had an early, unexplained, heart-related death
  • a thorough physical examination, including an evaluation of the skeletal frame for the ratio of arm/leg size to trunk size
  • an eye examination, including a "slit lamp" evaluation
  • heart tests such as an echocardiogram (a test that uses ultrasound waves to examine the heart and aorta).

FUN FACT!!: Abraham Lincoln, Mary Queen of Scots, and Tutankhamen were all said to have had Marfan Syndrome.

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2.) Marfan syndrome in children and adolescents: predictive and prognostic value of aortic root growth for screening for aortic complications. Groenink M, Rozendaal L, Naeff MS, Hennekam RC, Hart AA, van der Wall EE, Mulder BJ. Heart. 1998 Aug;80(2):163-9. PMID: 9813564
3.) Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis. Olivieri J, Smaldone S, Ramirez F. Fibrogenesis Tissue Repair. 2010 Dec 2;3(1):24. [Epub ahead of print] PMID: 21126338
4.) Fibrillin assemblies: extracellular determinants of tissue formation and fibrosis. Olivieri J, Smaldone S, Ramirez F. Fibrogenesis Tissue Repair. 2010 Dec 2;3(1):24. [Epub ahead of print] PMID: 21126338
5.) Cardiovascular characteristics in Marfan syndrome and their relation to the genotype. De Backer J. Verh K Acad Geneeskd Belg. 2009;71(6):335-71. Review. PMID: 20232788
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