Journal Article

<i>MYH11</i> mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

Hariyadarshi Pannu, Van Tran-Fadulu, Christina L. Papke, Steve Scherer, Yaozhong Liu, Caroline Presley, Dongchuan Guo, Anthony L. Estrera, Hazim J. Safi, Allan R. Brasier, G. Wesley Vick, A.J. Marian, C.S. Raman, L. Maximilian Buja and Dianna M. Milewicz

in Human Molecular Genetics

Volume 16, issue 20, pages 2453-2462
Published in print October 2007 | ISSN: 0964-6906
Published online July 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm201
MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

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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.

Journal Article.  5458 words.  Illustrated.

Subjects: Genetics and Genomics

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