Fibrillins
are a family of high sulphide containing glycoproteins that help create
elasticity within connective tissue, GC1 any
tissue that supports organs by forming a framework that binds different tissues
together. Connective tissues can also store fat and transport different
substances. It is made up of few cells but a large variety of
proteins that create the extracellular matrix. Fibroblast cells secrete the
extracellular matrix contents, which includes collagen, elastin and fibrillins.1 Fibrillins are made from amino acids joined together to form a peptide, whichGC2 
interact with each other within the peptide chain to create a highly specific
3D shape. If the configuration of the protein is changed, the functionality of
the protein may be affected, and it is likely that the protein will not be able
to perform its role within the body.

Fibrillins
form microfibrils 10-12 nm in length.2 There are two main sections
in the fibrillin protein; 43 calcium-binding epidermal growth factor-like
domains (cbEGF) and 8 transforming growth factor B binding protein-like
cysteine domains (TB).3,4 cbEGF domains are present in many
different proteins5, such as protein S, which works in the
anticoagulant system6, and Notch-3, a receptor involved in gene
expression.7

In
fibrillin-1, cbEGF domains have been shown to have antiparallel ? hairpin which
contains three disulphide bridges. Calcium binds to cbEGF domains using ligands
which arranges in a bipyramidal fashion. Six out of seven ligands are
intradomain oxygen atoms, in the form of oxygen atoms on side groups or as part
of a carbonyl. The seventh ligand has not yet been identified.8 Two
cbEGF domains are involved in the stabilisation of the other cbEGF domains and
do not directly bind to calcium. cbEGF domains are organised into a rod shape;
calcium has been shown to control the rigidity of the rod shape.3,4,9

The
TB domain comprises six antiparallel ? strands and 2 ? helices. It contains
four disulphide bridges which stabilise the structure. Six of the TB domains
are covalently bonded to cbEGF domains and has been shown to increase cbEGF
domain affinity to calcium atoms. TB domains bind to transforming growth factor
beta (TGF-?) proteins to store them within the matrix.6 Fibrillin-1 also
contains a region that is high in proline and is thought to act as a hinge
region.3

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Fibrillin-1
is secreted from fibroblasts3 and has multiple functions within the
extracellular matrix. The microfibrils that are formed from fibrillin-1 form
elastic fibres which also incorporate lysyl-oxidase, proteoglycans and elastin.
Fibrillin-1 is also present in tissues that do not contain elastin. The full
extent of fibrillin-1 protein functions and the processes involved within the
extracellular matrix has not yet been identified. Nonetheless,GC3 
some roles of fibrillin-1 are known. Fibrillin-1 provides a framework to
deposit tropoelastin, which is an important protein that allows elastic fibres
to stretch and recoil.10 The ? hairpin within cbEGF domains have
been shown to be a key component within this process. Additionally, fibrillin-1
microfibrils are shown to be elastic, which can indicate their use in tissues,
where elastin is not present, as an elastic fibre. The control of the rod shape
in fibrillin-1 through calcium can lead to the protein being able to flatten
the rod, elongating the protein, and can allow fibrillin-1 to behave in an
elastic nature. Fibrillin-1 can provide support to non-elastic tissues, and
anchors endothelial and epithelial tissues to elastic fibres.11

Calcium,
when bound to fibrillin-1, is shown to protect against proteolysis from
proteases within the matrix, such as elastase and trypsin. This is important
for fibrillin-1 to be able to function, as cbEGF domains that bind to calcium
allow fibrillin to carry out its various functions without degrading. Calcium is also important
in stabilising the fibrillin-1 structure; without calcium, microfibrils become
distorted.8 Another function that fibrillin-1 has is to store TGF-?,
which is inactive whilst bound to the fibrillin-1 within the microfibrils. TGF-? controls many cell processes including: cell proliferation,
cell motility and apoptosis.GC4 12
The structure of the TB domains allows fibrillin-1 to bind to TGF-?, thus the
structure of the TB domains allows fibrillin-1 to participate in the control of
these mechanisms.

The
FBN1 gene codes for both fibrillin-1 and asprosin, which is used in glucose
homeostasis.13 It is located at 15q21.1, at base pairs 48,408,406 to
48,645,788 on chromosome 15.12 The size of transcript is around 10kb
and the gene has 65 exons.11 Mutations in the FBN1 gene is known to cause
Marfan Syndrome (MFS). MFS is an autosomal dominant disease. Around three
quarters of cases are inherited, and a quarter occur from new mutations.14
There are over 3000 recorded mutations known to cause MFS,15 which
shows that the FBN1 gene is highly susceptive to genetic changes. Point
mutations are the most common mutations that take place in the gene, with the
occurrence at around 60%. Frameshifts are responsible for 13% of mutations, and
splicing errors also account for 13%.7 The mutations can be split
into two groups; one third lead to nonsense-mediated decay, where faulty mRNA
is broken down and results in a lower amount of the protein being produced, and
two thirds leads to improper folding of the fibrillin-1 protein.7

The mutations that bring about improper
folding can affect disulphide bridges, amino acid residues involved in calcium
bonding or other amino acids that affect the conformation of fibrillin-1. These
mutations change the conformation of the fibrillin-1 protein and can lower the
affinity for calcium, thus the protein is not protected from proteolysis and
the stability of the protein is disrupted. Fibrillin-1 may not be able to bind
to TGF-? if the 3D shape of fibrillin-1 changes, leading to fibrillin-1 being
unable to store TGF-? within the extracellular matrix. MFS sufferers tend to
have a delayed secretion of fibrillin-1, though some have normal secretion
which supports that fibrillin-1 has compromised effectiveness in the
extracellular environment. Some MFS sufferers have fibrillin-1 that is seen to
have undergone glycosylation which suggests that their fibrillin-1 does not
leave the cell and is retained in the endoplasmic reticulum.3,16 MFS
can be caused hundreds of different known mutations, so the nature of the mutation will affect the functionality and
vesicular trafficking of fibrillin-1.

MFS is the most common genetic disease
affecting connective tissue. It has a frequency of 1 in 5000 people.14
MFS sufferers tend to be taller and slenderer  than
family members that are not affected and have very long fingers and toes
(arachnodactyly). Over half of sufferers also develop scoliosis- abnormal
curving of the spine. The sternum can protrude outwards or be sunken and
fingers may be bent, as well as joint hypermobility. Spinal abnormalities are
due to TGF-? not being stored in the mutant fibrillin-1, leading to tissues
overgrowing and instability within the tissues. This can also lead to
cardiovascular problems, some of which can be very serious and life
threatening. Aortic dilation (enlargement of the aorta) or aortic aneurysm
(bulging of aorta walls) can occur. This puts the MFS sufferer at risk of
aortic dissection, where the aorta wall can rupture or tear. This is due to
fragmentation and disorganisation in the elastic fibres, as tropoelastin
deposition is disrupted. If the ascending aorta tears it is life threatening
and requires immediate surgery. A tear in the descending aorta is not as
dangerous, however still puts the vital organs at risk of reduced blood flow.
Other cardiac problems include leakage of the mitral valve, causing an
irregular heartbeat and chest pain. 14,17,18,19

MFS can cause problems with the eyes. Near
sightedness is extremely common and often sufferers get ectopia lentis, where
the lens detaches from the centre of the eyeball. They can develop cataracts or
glaucoma early in life, which leads to blindness if untreated. Some MFS
sufferers develop pockets of air in the lung and spontaneous lung collapse.
Other diseases can have very similar symptoms to MFS, however are due to
mutations in genes for other very similar proteins, such as fibrillin-2. MFS
has no cure as it is a genetic disease and treatments are directed towards
specific symptoms of MFS. MFS has a high survival rate, though some more
severely affected die in infancy.14,17,18,19

Figure 1 source: https://www.sciencedirect.com/science/article/pii/S0022283698925360

Figure 2 source: http://www.sciencedirect.com/science/article/pii/S0167488900000859?via%3Dihub

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