MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.

TitleMYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II.
Publication TypeJournal Article
Year of Publication2007
AuthorsPannu, H, Tran-Fadulu, V, Papke, CL, Scherer, S, Liu, Y, Presley, C, Guo, D, Estrera, AL, Safi, HJ, Brasier, AR, G Vick, W, Marian, AJ, Raman, CS, L Buja, M, Milewicz, DM
JournalHum Mol Genet
Volume16
Issue20
Pagination2453-62
Date Published2007 Oct 15
ISSN0964-6906
KeywordsAdult, Amino Acid Sequence, Angiotensin II, Aortic Aneurysm, Thoracic, Child, Preschool, Ductus Arteriosus, Patent, Female, Genetic Testing, Humans, Insulin-Like Growth Factor I, Male, Middle Aged, Models, Molecular, Molecular Sequence Data, Mutation, Myosin Heavy Chains, Pedigree, Sequence Homology, Amino Acid, Vascular Diseases
Abstract

Non-syndromic thoracic aortic aneurysms and dissections (TAADs) are inherited in an autosomal dominant manner in approximately 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-beta expression or downstream targets was observed. Enhanced expression of angiotensin-converting enzyme and markers of Angiotensin II (Ang II) vascular inflammation (macrophage inflammatory protein-1alpha and beta) 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.

DOI10.1093/hmg/ddm201
Alternate JournalHum Mol Genet
PubMed ID17666408
PubMed Central IDPMC2905218
Grant ListS10 RR019186 / RR / NCRR NIH HHS / United States
R01 HL088498 / HL / NHLBI NIH HHS / United States
R01 HL062594 / HL / NHLBI NIH HHS / United States
M01RR02558 / RR / NCRR NIH HHS / United States
R01 HL088498-01A1 / HL / NHLBI NIH HHS / United States
R01 HL068884-05 / HL / NHLBI NIH HHS / United States
S10 RR19186 / RR / NCRR NIH HHS / United States
R01 HL068884 / HL / NHLBI NIH HHS / United States
P50HL08379-01 / HL / NHLBI NIH HHS / United States
M01 RR002558 / RR / NCRR NIH HHS / United States
R01 HL62594 / HL / NHLBI NIH HHS / United States

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