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 another group of families with thoracic aneurysm without distinct clinical features, genetic defects were identified in the so-called non-syndromic familial thoracic aneurysm genes including the MYH11, MYLK and ACTA2 that affect smooth muscle cell (SMC) functioning (Kuang et al. 2012; Pannu et al. 2007; Renard et al. 2013; Wang et al. 2010). These may also affect TGF-β signaling, like ACTA2 mutations, occurring in 16 % of patients with familial thoracic aortic aneurysm and in sporadic thoracic aortic aneurysms and dissections associated with medial degeneration, focal medial smooth muscle cell hyperplasia and proliferation, and stenotic arteries in the vaso-vasorum (Guo et al. 2007; Morisaki et al. 2009; Renard et al. 2013). "
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    ABSTRACT: Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.
    Human Genetics 05/2015; 134(8). DOI:10.1007/s00439-015-1567-0 · 4.82 Impact Factor
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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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    ABSTRACT: Smooth muscle (SM) exhibits a highly organized structural hierarchy that extends over multiple spatial scales to perform a wide range of functions at the cellular, tissue, and organ levels. Early efforts primarily focused on understanding vascular SM (VSM) function through biochemical signaling. However, accumulating evidence suggests that mechanotransduction, the process through which cells convert mechanical stimuli into biochemical cues, is requisite for regulating contractility. Cytoskeletal proteins that comprise the extracellular, intercellular, and intracellular domains are mechanosensitive and can remodel their structure and function in response to external mechanical cues. Pathological stimuli such as malignant hypertension can act through the same mechanotransductive pathways to induce maladaptive remodeling, leading to changes in cellular shape and loss of contractile function. In both health and disease, the cytoskeletal architecture integrates the mechanical stimuli and mediates structural and functional remodeling in the VSM. Anat Rec, 297:1758–1769, 2014. © 2014 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 09/2014; 297(9). DOI:10.1002/ar.22983 · 1.54 Impact Factor
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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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    ABSTRACT: Ongoing studies using genomic microarrays and next-generation sequencing have demonstrated that the genetic contributions to cardiovascular diseases have been significantly ignored in the past. The aim of this study was to identify rare copy number variants in individuals with congenital pulmonary atresia (PA). Based on the hypothesis that rare structural variants encompassing key genes play an important role in heart development in PA patients, we performed high-resolution genome-wide microarrays for copy number variations (CNVs) in 82 PA patient-parent trios and 189 controls with an Illumina SNP array platform. CNVs were identified in 17/82 patients (20.7%), and eight of these CNVs (9.8%) are considered potentially pathogenic. Five de novo CNVs occurred at two known congenital heart disease (CHD) loci (16p13.1 and 22q11.2). Two de novo CNVs that may affect folate and vitamin B12 metabolism were identified for the first time. A de novo 1-Mb deletion at 17p13.2 may represent a rare genomic disorder that involves mild intellectual disability and associated facial features. Rare CNVs contribute to the pathogenesis of PA (9.8%), suggesting that the causes of PA are heterogeneous and pleiotropic. Together with previous data from animal models, our results might help identify a link between CHD and folate-mediated one-carbon metabolism (FOCM). With the accumulation of high-resolution SNP array data, these previously undescribed rare CNVs may help reveal critical gene(s) in CHD and may provide novel insights about CHD pathogenesis.
    PLoS ONE 05/2014; 9(5):e96471. DOI:10.1371/journal.pone.0096471 · 3.23 Impact Factor
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