Human Molecular Genetics Advance Access originally published online on July 31, 2007
Human Molecular Genetics 2007 16(20):2453-2462; doi:10.1093/hmg/ddm201
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MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II
1 Department of Internal Medicine and Institute of Molecular Medicine, 2 Department of Cardiothoracic and Vascular Surgery, 3 Department of Biochemistry and 4 Department of Pathology, The University of Texas Health Science Center at Houston, Houston, TX, USA, 5 Human Genetics Center and 6 Lillie Frank Abercrombie Section of Pediatric Cardiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA and 7 Department of Medicine, The University of Texas Medical Branch, Galveston, TX, USA
* To whom correspondence should be addressed at: Department of Internal Medicine and Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin, MSB 6.100, Houston, TX 77030, USA. Tel: +1 7135006725; Fax: +1 7135000693; Email: dianna.m.milewicz{at}uth.tmc.edu
Received May 23, 2007; Accepted July 19, 2007
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-ß expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1
and ß) 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.