Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD.

Abstract

BACKGROUND:

Thoracic aortic aneurysm/dissection (TAAD) is a common phenotype that may occur as an isolated manifestation or within the constellation of a defined syndrome. In contrast to syndromic TAAD, the elucidation of the genetic basis of isolated TAAD has only recently started. To date, defects have been found in genes encoding extracellular matrix proteins (fibrillin-1, FBN1; collagen type III alpha 1, COL3A1), proteins involved in transforming growth factor beta (TGFβ) signaling (TGFβ receptor 1 and 2, TGFBR1/2; and SMAD3) or proteins that build up the contractile apparatus of aortic smooth muscle cells (myosin heavy chain 11, MYH11; smooth muscle actin alpha 2, ACTA2; and MYLK).

METHODS AND RESULT:

In 110 non-syndromic TAAD patients that previously tested negative for FBN1 or TGFBR1/2 mutations, we identified 7 ACTA2 mutations in a cohort of 43 familial TAAD patients, including 2 premature truncating mutations. Sequencing of MYH11 revealed an in frame splice-site alteration in one out of two probands with TAA(D) associated with PDA but none in the series of 22 probands from the cohort of 110 patients with non-syndromic TAAD. Interestingly, immunohistochemical staining of aortic biopsies of a patient and a family member with MYH11 and patients with ACTA2 missense mutations showed upregulation of the TGFβ signaling pathway.

CONCLUSIONS:

MYH11 mutations are rare and typically identified in patients with TAAD associated with PDA. ACTA2 mutations were identified in 16% of a cohort presenting familial TAAD. Different molecular defects in TAAD may account for a different pathogenic mechanism of enhanced TGFβ signaling.

• Authors: Marjolijn Renard, Bert Callewaert, Machteld Baetens, Laurence Campens, Kay MacDermot, Jean-Pierre Fryns, Maryse Bonduelle, Harry C Dietz, Isabel Mendes Gaspar, Diogo Cavaco, Eva-Lena Stattin, Constance Schrander-Stumpel, Paul Coucke, Bart Loeys, Anne De Paepe, Julie De Backer
• Journal: International journal of cardiology (Int J Cardiol) Vol. 165 Issue 2 Pg. 314-21 (May 10 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 21937134 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ACTA2 protein, human
• Actins
• MYH11 protein, human
• Transforming Growth Factor beta
• Myosin Heavy Chains

Topics

• Actins (chemistry, genetics)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aortic Dissection (diagnosis, genetics)
• Aortic Aneurysm, Thoracic (diagnosis, genetics)
• Cohort Studies
• Female
• Humans
• Male
• Middle Aged
• Mutation (genetics)
• Myosin Heavy Chains (chemistry, genetics)
• Pedigree
• Signal Transduction (genetics, physiology)
• Transforming Growth Factor beta (genetics, physiology)
• Up-Regulation (genetics)