TY - JOUR
T1 - Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD
AU - Renard, Marjolijn
AU - Callewaert, Bert
AU - Baetens, MacHteld
AU - Campens, Laurence
AU - MacDermot, Kay
AU - Fryns, Jean Pierre
AU - Bonduelle, Maryse
AU - Dietz, Harry C.
AU - Gaspar, Isabel Mendes
AU - Cavaco, Diogo
AU - Stattin, Eva Lena
AU - Schrander-Stumpel, Constance
AU - Coucke, Paul
AU - Loeys, Bart
AU - De Paepe, Anne
AU - De Backer, Julie
N1 - Funding Information:
This study was supported in part by the Fund for Scientific Research, Flanders (Belgium) [ G.0094.06 ]; Fighting Aneurysmal Disease [ EC-FP7 ]; the Special Research Fund of the Ghent University [ BOF10/GOA/005 ]; a Methusalem grant from the Flemish government and the Ghent University to ADP [08/01M01108] and the National Institutes of Health (NIH) and Howard Hughes Medical Institute (HHMI). B. Loeys, J. De Backer, B. Callewaert and M. Renard are/were, respectively, senior clinical investigators (BL and JDB), postdoctoral fellow (BC) and junior scientific investigator (MR) supported by the Fund for Scientific Research, Flanders (Belgium).
PY - 2013/5/10
Y1 - 2013/5/10
N2 - 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.
AB - 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.
KW - Myosin heavy chain 11
KW - Smooth muscle α-actin
KW - TGFβ signaling
KW - Thoracic aortic aneurysm
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U2 - 10.1016/j.ijcard.2011.08.079
DO - 10.1016/j.ijcard.2011.08.079
M3 - Article
C2 - 21937134
AN - SCOPUS:84876664370
SN - 0167-5273
VL - 165
SP - 314
EP - 321
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 2
ER -