Genetic and molecular basis of BAV-TA
Transcript Genetic and molecular basis of BAV-TA
A permanent dilatation of 50% or more compared with
the expected normal diameter of the vessel.
An arterial dilatation less then 50% of the original
A diffuse enlargement in several arterial
segments greater than 50% in diameter
1. Thoracic Aortic Aneurysms
- Marfan syndrome(MFS)
- Bicuspid aortic valve(BAV)
- Familial thoracic aortic aneurysm syndrome
2. Abdominal Aortic Aneurysms
- MFS is a systemic disorder of connective tissue with protean
manifestations, with the skeletal, ocular, and cardiovascular systems most
- The hallmark of MFS is abnormality of the medial layer of the aortic wall
and the most threatening consequence of MFS is dilatation of the aortic
root and the ascending aorta, which, if untreated, can result in fatal aortic
dissection or rupture.
- Autosomal-dominant with complete penetrance.
- FBN1 mutations were linked to the majority of the cases of MFS
- In addition, a distinct gene on chromosome 3p24 (TGFBR2) was linked to
another family with MFS.
It is possible that the genes responsible for MFS may also
account for the development of the associated thoracic aortopathy,
because of a shared embryological origin of the aortic valve and the
ascending aorta from the cardiac neural crest cells.
TGFBR1, TGFBR2, SMAD3
- TGFβR1,2: Four missense mutations
that affect the kinase domains,
causing MFS and familial thoracic
aortic aneurysm and aortic
dissections (TAAD), have been
- SMAD3: One frameshift mutation and
three missense mutations were
identified in individuals with
FTAAD, located in exons 2,5, and 6
Dysregulation of ECM, proliferation
and differentiation in aortic wall
Bicuspid aortic valve disease (BAVD)
- BAVD is the most common congenital cardiac malformation, affecting
1–2% of the population.
- BAVD is highly associated with other congenital aorta abnormalities, such
as coarctation , dilatation of the aortic root or ascending aorta and may
progress to frank thoracic aortic aneurysms and aortic dissection.
- The histopathology in such cases is similar to that of patients with MFS
who also have abnormal FBN1 content in their aortic wall.
- Fibrillin-1 deficiency is also observed in the pulmonary arteries of BAV
patients and main pulmonary artery dilatation has been noted to occur in
association with BAV in the absence of pulmonary valve abnormality.
Hemodynamic contributions in BAV-TA
- Increased expression of MMP2 and a higher MMP2 to TIMP1 activity in tissue
samples from aortic aneurysms in BAV patients.
weakening of aortic wall structural integrity, loss of aortic elasticity,
progressive aortic dilatation, and aneurysm and/or dissection .
- Reduction of endothelial nitric oxide synthase (eNOS) protein expression, with
site-dependent variability, which is probably triggered by variations in shear
stress along the aortic wall.
cytosolic accumulation of HTRA2/Omi, a
proapoptotic mitochondrial serine protease, which presumably mediates VSMC
apoptosis in BAV aortas.
- ECM remodelling occurs early in BAV(during development and valvulogenesis):
collagen, laminin , fibrillin and fibulin reduction and increases in fibronectin
and tenascin expression.
increased Bcl-2-modifying factor-Bcl-2
binding (Bmf-Bcl2), a known matrix-dependent proapoptotic, enhanced VSMC
BAVD is the result of intrinsic defects in the ECM rather than a secondary
consequence of valvular dysfunction.
- Dilatation of the ascending thoracic aorta can be found in young adults
with a bicuspid aortic valve but without significant valvular stenosis or
- BAVD patients who have undergone aortic valve replacement can develop
ascending thoracic aortic aneurysms at a later date.
Genetic and molecular basis of BAV-TA
- BAV is a heritable trait: approximately 9% prevalence amongst first
degree relatives, and up to 24% in families with more than one
affected family member.
- Genetic heterogeneity with variable patterns of inheritance.
Major related genes:
-Transcriptional regulator NOTCH1 gene at chromosome 9q34.3
-Homozygous deletion of the eNOS (Nos3) gene
-Cardiac homeobox Nkx2-5 haploinsufficiency
-Deletion of the cardiac transcription factor GATA5 (essential factor in
cardiogenesis and aortic valve development, endocardial cell
- Activation of inflammatory pathways plays a critical role in the development
- Notch1 signaling is a significant regulator of the inflammatory response.
- Overexpression of NOTCH1 increasing inflammatory response in the aorta.
Genetic and molecular basis of BAV-TA
- BAV has been observed to occur more frequently in patients with
thoracic aortic aneurysm who have mutations in the FBN1 and
ACTA2 genes .
- A single nucleotide substitution in the TGFBR2 gene, c1159G>A,
which results in an amino acid change (i.e. missense mutation) and
destabilizes the mutant TGFBR2 protein structure of the aortic media,
was segregated in a family with BAV and proximal aortic aneurysm .
- Genome-wide marker-based linkage analyses have provided evidence
on the genetic basis of BAV-TA with some families with BAV and
ascending aortic aneurysms showing linkage to chromosome 15q2526 . although the causal gene(s) are yet to be identified.
- ACTA2 mutated in 14-20% of people with thorasic aortic aneurysm
The ACTA2 gene
smooth muscle alpha (α)-2 actin, which is
found in vascular smooth muscle cells.(walls of the aorta)
Sarcomeres formation which are necessary for muscles to contract.
allows the arteries to maintain their shape instead of stretching out
as blood is pumped through them.
ACTA2 dominant negative mutations
Abnormal stretching of
the aorta results in the aortic dilatation, aneurysms, and dissections.
- Recently, a comparative study on global gene expression levels was
performed in aortic tissues from patients with bicuspid or tricuspid aortic
valve, with and without thoracic aortic aneurysm, Only 7 genes showed
differential expression in 2 groups:
The 4 upregulated genes
The 3 downregulated genes
LEFTY2 (a TGF-β family member),
FRAS1 (a member of ECM family of protein),
SHC4(Src Homology 2 Domain Containing)
DAPK3 (a proapoptotic gene).
VEGFC (a member of VEGF family)
NFASC (a member of the L1 family of
LSP1 (lymphocyte-specific protein-1).
- BAV patients with aortic dilatation showed an almost exclusive
expression of the TGF-β binding proteins LTBP3/4, ADAMTSL1 and
an alternatively spliced isoform of Fibronectin-1 (FN1).
Likely, they have impaired TGF-β mediated splicing mechanisms of
fibronectin transcript, thereby leading to altered fibronectin expression
in the aortic aneurysm tissue and consequently contributing to the
increased susceptibility to aortopathy development in BAV patients.
Familial thoracic aortic aneurysm syndrome
- Familial TAAD is expected to cause about 20% of all cases of thoracic
aortic aneurysms and dissections.
- This disorder can occur in conjunction with other genetic syndromes
including Marfan syndrome, Loeys-Dietz syndrome, Ehlers-Danolos,
and other related syndromes.
- Not have identifiable congenital abnormalities.
- Absence of overt connective tissue disorders.
- Most pedigrees suggested autosomal-dominant of inheritance.
- Variability in the expression and penetrance
- Genetic heterogeneity
Genetics of familial thoracic aortic aneurysm syndrome
- Account for 2% of non-syndromic TAAD.
- Heterozygous MYH11 mutations result in thoracic aortic aneurysms and are
thought to act via a dominant negative mechanism with wild-type MYH11.
- MYLK encodes three gene products
expressed from separate promoters, with
two isoforms containing the catalytic and
CaM-binding domains and a third, small,
non-catalytic protein called telokin (that
affects calcium sensitivity of
- A c.4438C>T (p.Arg1480Ter) mutation located in the
MLCK kinase domain leads to either nonsense-mediated
decay or a truncated protein .
- Two other missense alterations, c.5260G>A and
c.5275T>C, disrupt in calmodulin-binding sequence and lead
to decreased MLCK function
Abdominal Aortic Aneurysms(AAA)
- AAA is usually deﬁned as infrarenal aortic diameter >30mm.
- AAAs are typically associated with aging and atherosclerosis.
- Gender plays a role; men are 10 times more likely than women to have an AAA of
4 cm or greater, BUT women with an AAA have a significantly greater risk of
rupture than men.
- Approximately 20 % of the patients with an abdominal aortic aneurysm (AAA)
have a positive family history for aneurysms.
- Those having a first-degree relative with an AAA have an increased risk of 13–
32% compared with the 2–5% risk in the general population.
- Those with familial aneurysms tend to be younger and have higher rates of rupture
than those with sporadic aneurysms.
Pathophysiology of AAA
Biochemical wall stress.
- Natural reduction in the number of elastin layers in the aortic wall in the
- Decrease in the collagen content from the proximal to the distal aorta.
- A calcified plaque, a common feature of AAAs, causes increased local
wall stress due to the focal stiffness
Destructive remodeling of the elastic media of the aortic wall
Infiltration of inflammatory cells, including B lymphocytes, T lymphocytes, and
Increased immunoreactivity for elastolytic matrix metalloproteases (MMP),
particularly MMP-2, MMP-9, and MMP-12, secreted by the infiltrating
macrophages, and cytokines.
Genetic basis of AAA
- Genes associated with the familial thoracic aortic aneurysm play a role in the
degenerative changes of the extracellular matrix of the abdominal aortic
wall underlying the formation of AAA.
- In addition, an association between abdominal aneurysm and the c.665C>T
variant in MTHFR have been investigated.
- There is higher incidence of the allele subtype HLA-DR B1*0401 and HLADQA1*0102 in the AAA patient. In contrast, the HLA-DR B1*01 allele
tended to behave as a protective factor for AAA.
- Serum folate deficiency and hyperhomocysteinemia were associated with an
increased risk of AAA
- ER stress induced by homocysteine increases gene expression of MMP-3
(ER stress-induced apoptosis in aortic wall cells)
Atherosclerotic lesions, such as those seen in the apo-E mutation, serve as
the initial insult leading to a chronic inflammatory state. But not
sufficient to induce the formation of aneurysms, a significant endothelial
dysfunction (such as lack of the critical endothelial regulator nitric oxide)
may be the second factor that accelerates the process of AAA formation.
Mice were more hypertensive than control
wild-type mice, and a significant proportion of
these mice developed an AAA. The
development of the AAA was not simply owing
to hypertension, because lowering the blood
pressure to levels seen in the control mice had
no effect in reducing aneurysm development!
Genetic Associations by meta-analyses.
LRP1, LDLR, SORT1 affect cholesterol metabolism and atherosclerosis.
LRP1 has other important regulatory roles, including regulation of extracellular
matrix breakdown by the endocytosis of proteinases.
LPA produces lipoprotein A, which increases cardiovascular risk.
IL6R polymorphisms alter cardiovascular risk, possibly through inﬂammation.
MMP3 affects atherosclerosis and tissue remodelling.
AGTR1 affects blood pressure, which is consistent with the association
between hypertension and AAA.
DAB2IP is a tumour suppressor gene involved in cell signalling, survival,
migration, maturation, and apoptosis.
- Inhibitors of MMPs (doxycycline and BB-94) or other proteases such as
cathepsins and plasminogen-activator inhibitor (PAI-1) offers a tremendous
therapeutic strategy to prevent AAA enlargement .
- Inflammation plays an integral role in the development of AAA and expression
of the inflammatory molecule, cyclooxygenase (COX)-2, is increased in
aneurysmal tissues: NSAIDs (celecoxib) decreased the incidence and severity
of AAA formation
- C-Jun N-Terminal Kinase (JNK) is highly active in human AAA walls and
specific inhibition of JNK can significantly suppress the secretion of MMP-9
and prevent collagen degradation. JNK inhibition may play a significant role
in impeding the progression of AAA.
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Associations: Mostly False? A Systematic Review and Meta-analysis. Eur
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in familial and sporadic abdominal aortic aneurysm. Hum Genet (2015)
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bicuspid aortic valve associated thoracic aortopathy: a link to phenotype
heterogeneity.Ann Cardiothorac Surg 2013;2(1):83-91
Suman Annambhotla, Sebastian Bourgeois et al. Recent Advances in
Molecular Mechanisms of Abdominal Aortic Aneurysm Formation. World
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