Mutations in transforming growth factor-β receptor type II cause familial thoracic aortic aneurysms and dissections

Academic Article


  • Background - A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24-25, we sequenced the gene for transforming growth factor-β receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD. Methods and Results - We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases. We found TGFBR2 mutations in 4 unrelated families with familial TAAD who did not have Marfan syndrome. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, all 4 mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation "hot spot" for familial TAAD. Despite identical mutations in the families, assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. Conclusion - Germline TGFBR2 mutations are responsible for the inherited predisposition to familial TAAD in 5% of these cases. Our results have broad implications for understanding the role of TGF-β signaling in the pathophysiology of TAAD. © 2005 American Heart Association, Inc.
  • Authors

    Published In

  • Circulation  Journal
  • Digital Object Identifier (doi)

    Author List

  • Pannu H; Fadulu VT; Chang J; Lafont A; Hasham SN; Sparks E; Giampietro PF; Zaleski C; Estrera AL; Safi HJ
  • Start Page

  • 513
  • End Page

  • 520
  • Volume

  • 112
  • Issue

  • 4