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

Abstract

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-beta 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.

CONCLUSIONS:

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-beta signaling in the pathophysiology of TAAD.

• Authors: Hariyadarshi Pannu, Van Tran Fadulu, Jessica Chang, Andrea Lafont, Sumera N Hasham, Elizabeth Sparks, Philip F Giampietro, Christina Zaleski, Anthony L Estrera, Hazim J Safi, Sanjay Shete, Marcia C Willing, C S Raman, Dianna M Milewicz
• Journal: Circulation (Circulation) Vol. 112 Issue 4 Pg. 513-20 (Jul 26 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 16027248 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II

Topics

• Adult
• Aged
• Aortic Dissection (genetics)
• Aortic Aneurysm, Thoracic (genetics)
• Female
• Humans
• Male
• Middle Aged
• Mutation
• Polymorphism, Single Nucleotide
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (chemistry, genetics)
• Signal Transduction