title: 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).
  
  
  RESULTS
  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.affiliation: Center for Medical Genetics, University Hospital of Ghent, Ghent, Belgium. Marjolijn.Renard@ugent.be
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.forename: Machteld
authors.initials: M
authors.lastname: Baetens
authors.forename: Laurence
authors.initials: L
authors.lastname: Campens
authors.forename: Kay
authors.initials: K
authors.lastname: MacDermot
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonduelle
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.forename: Isabel Mendes
authors.initials: IM
authors.lastname: Gaspar
authors.forename: Diogo
authors.initials: D
authors.lastname: Cavaco
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Constance
authors.initials: C
authors.lastname: Schrander-Stumpel
authors.forename: Paul
authors.initials: P
authors.lastname: Coucke
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
mesh_terms: D000199:Actins / Q000737:chemistry / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000784:Aortic Dissection / Q000175:diagnosis / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C509903:MYH11 protein, human; D016212:Transforming Growth Factor beta; D018995:Myosin Heavy Chains