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2015 ; 7
(1
): 105-115
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gab.com Text
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Molecular mechanisms of inherited thoracic aortic disease - from gene variant to
surgical aneurysm
#MMPMID28509973
Robertson E
; Dilworth C
; Lu Y
; Hambly B
; Jeremy R
Biophys Rev
2015[Mar]; 7
(1
): 105-115
PMID28509973
show ga
Aortic dissection is a catastrophic event that has a high mortality rate.
Thoracic aortic aneurysms are the clinically silent precursor that confers an
increased risk of acute aortic dissection. There are several gene mutations that
have been identified in key structural and regulatory proteins within the aortic
wall that predispose to thoracic aneurysm formation. The most common and well
characterised of these is the FBN1 gene mutation that is known to cause Marfan
syndrome. Others less well-known mutations include TGF-?1 and TGF-?2 receptor
mutations that cause Loeys-Dietz syndrome, Col3A1 mutations causing Ehlers-Danlos
Type 4 syndrome and Smad3 and-4, ACTA2 and MYHII mutations that cause familial
thoracic aortic aneurysm and dissection. Despite the variation in the proteins
affected by these genetic mutations, there is a unifying pathological end point
of medial degeneration within the wall of the aorta characterised by vascular
smooth muscle cell loss, fragmentation and loss of elastic fibers, and
accumulation of proteoglycans and glycosaminoglycans within vascular smooth
muscle cell-depleted areas of the aortic media. Our understanding of these
mutations and their post-translational effects has led to a greater understanding
of the pathophysiology that underlies thoracic aortic aneurysm formation. Despite
this, there are still many unanswered questions regarding the molecular
mechanisms. Further elucidation of the signalling pathways will help us identify
targets that may be suitable modifiers to enhance treatment of this often fatal
condition.