Pannu, H. et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor I and angiotensin II. Hum. Mol. Genet. 16, 2453-2462

Texas A&M University - Galveston, Galveston, Texas, United States
Human Molecular Genetics (Impact Factor: 6.39). 11/2007; 16(20):2453-62. DOI: 10.1093/hmg/ddm201
Source: PubMed


Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in ∼20% of cases.
Familial TAAD is genetically heterogeneous and four loci have been mapped for this disease to date, including a locus at 16p
for TAAD associated with patent ductus arteriosus (PDA). The defective gene at the 16p locus has recently been identified
as the smooth muscle cell (SMC)-specific myosin heavy chain gene (MYH11). On sequencing MYH11 in 93 families with TAAD alone and three families with TAAD/PDA, we identified novel mutations in two families with TAAD/PDA,
but none in families with TAAD alone. Histopathological analysis of aortic sections from two individuals with MYH11 mutations revealed SMC disarray and focal hyperplasia of SMCs in the aortic media. SMC hyperplasia leading to significant
lumen narrowing in some of the vessels of the adventitia was also observed. Insulin-like growth factor-1 (IGF-1) was upregulated
in mutant aortas as well as explanted SMCs, but no increase in transforming growth factor-β expression or downstream targets
was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation
(macrophage inflammatory protein-1α and β) were also found. These data suggest that MYH11 mutations are likely to be specific to the phenotype of TAAD/PDA and result in a distinct aortic and occlusive vascular pathology
potentially driven by IGF-1 and Ang II.

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    • "In these syndromes as well as other cases of TAAD, a switch from a contractile phenotype to a synthetic phenotype in VSMCs is observed leading to subsequent dilation of the aorta (Lesauskaite et al., 2001; Huang et al., 2010). More recently, genetic mapping studies have found mutations in myosin heavy chain 11 (Zhu et al., 2006; Pannu et al., 2007) and SM a-actin (Guo et al., 2007) also lead to TAAD. These mutations resulted in decreased contractile function and loss of regulation of blood pressure (Schildmeyer et al., 2000). "
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    • "Of the 12 genes contained in the 16p13.1 region, MYH11 has been previously associated with heart disease. Mutations in MYH11 cause thoracic aortic aneurysm/dissection, and recurrent 16p13.1 duplications confer a risk for aortic dissection [7], [13], [36]. The 1-Mb deletion at 17p13.2 covers a gene-rich region (with 30 annotated genes), suggesting that this CNV is potentially pathogenic. "
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    • "These disorders are characterized by aortic aneurysms, which are abnormal enlargements of the aorta caused by thinning of the vessel wall (Dietz et al., 1991; Dietz and Pyeritz, 1995; Pope et al., 1975). Also, genetic mutations in smooth muscle contractile proteins can result in hereditary vascular anomalies, such as patent ductus arteriosus, aortic aneurysms and aortic dissections (Guo et al., 2007: Pannu et al., 2007; Zhu et al., 2006). Also, mutations in genes encoding transforming growth factor beta (TGFβ) receptors (TGFBR1 or TGFBR2) have been shown to cause "
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