Washington: Scientists claim to have
finally discovered the causes for the stiff skin syndrome, a
breakthrough which may pave the way for new treatments.
A team at Johns Hopkins University has studied the
genetics of stiff skin syndrome to learn about scleroderma,
a condition that leads to hardening of the skin as well as
other debilitating and often life-threatening problems, the
`Science Translational Medicine` journal reported.
"Scleroderma is a common and often devastating
condition yet its cause remains mysterious. My greatest hope
is that this work will facilitate the development of new and
better treatments," lead scientist Harry C Dietz said.
Also known as systemic sclerosis, scleroderma
generally affects previously healthy young adults, causing
scarring of skin and internal organs that can lead to heart
and lung failure.
"Most often individuals with scleroderma do not
have other affected family members, precluding use of genetic
techniques to map the underlying genes. Instead we turned to a
rare but inherited form of isolated skin fibrosis called stiff
skin syndrome, hoping to gain a foothold regarding cellular
mechanisms that might prove relevant," Dietz said.
A number of clues led Dietz and his team to strongly
suspect a role for the connective tissue protein fibrillin-1
in these skin conditions. First, excess collagen is a hallmark
feature of both stiff skin syndrome and scleroderma.
While studying Marfan syndrome, a condition caused by
a deficiency of fibrillin-1, the researchers discovered that
fibrillin-1 regulates the activity of TGFbeta, a molecule that
induces cells to make more collagen.
So Dietz`s team examined patients with stiff skin
syndrome and found them to have excessive amounts of
fibrillin-1 in the skin.
The researchers then sequenced the fibrillin-1 gene
in these same patients and found all the stiff skin syndrome
mutations clustered in a single region of the fibrillin-1
protein known to interact with neighboring cells.
Further examination showed that these mutations
prevent fibrillin-1 from interacting with neighboring cells
and lead to increased amounts and activity of TGFbeta, which
causes excessive collagen outside cells.
"It appears that fibriillin-1 helps to inform cells
about the quality of their surroundings and also provides a
mechanism -- by concentrating TGFbeta -- to induce extra
cellular matrix production if the cell senses a deficiency.
"A breakdown in signaling coupled with excessive
fibrillin-1 and TGFbeta leads to a perfect storm for skin
fibrosis in stiff skin syndrome," Dietz said.