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Circulation. 2005 Jul 26;112(4):513-20. Epub 2005 Jul 18.

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

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  • 1Department of Internal Medicine, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA.

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.

PMID:
16027248
[PubMed - indexed for MEDLINE]
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