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(Circulation. 2005;112:513-520.)
© 2005 American Heart Association, Inc.

Genetics

Mutations in Transforming Growth Factor-ß Receptor Type II Cause Familial Thoracic Aortic Aneurysms and Dissections

Hariyadarshi Pannu, PhD; Van Tran Fadulu, MS; Jessica Chang; Andrea Lafont, BS; Sumera N. Hasham, PhD; Elizabeth Sparks, MS; Philip F. Giampietro, MD, PhD; Christina Zaleski, MS; Anthony L. Estrera, MD; Hazim J. Safi, MD; Sanjay Shete, PhD; Marcia C. Willing, MD, PhD; C.S. Raman, PhD; Dianna M. Milewicz, MD, PhD

From the Department of Internal Medicine and Institute of Molecular Medicine (H.P., V.T.F., J.C., S.N.H., D.M.M.), the Department of Cardiothoracic and Vascular Surgery (A.L.E., H.J.S.), and the Structural Biology Research Center (C.S.R.), the University of Texas Health Science Center at Houston; the Department of Internal Medicine (E.S.), Cardiology Division, The Ohio State University, Columbus; the Department of Medical Genetic Services (P.F.G., C.Z.), Marshfield Clinic, Marshfield, Wis; the Department of Epidemiology (S.S.), the University of Texas M.D. Anderson Cancer Center, Houston, Tex; and the Department of Pediatrics, the University of Iowa (M.C.W.), Iowa City.

Correspondence to Dr Dianna Milewicz, 6431 Fannin, MSB 4.202, Houston, TX 77030. E-mail Dianna.M.Milewicz{at}uth.tmc.edu

Received December 8, 2004; de novo received January 19, 2005; revision received April 12, 2005; accepted April 18, 2005.

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-ß 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-ß signaling in the pathophysiology of TAAD.

Key Words: aneurysm • aorta • genetics • dissection • receptors, transforming growth factor beta

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