Fibrillins tissues can also store fat and

Fibrillins are a family of
high sulphide containing glycoproteins that help create elasticity within
connective tissue, 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, which 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 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.3Fibrillin-1 is secreted from
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, 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

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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.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

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.

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

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.14,17,18,19


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