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


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.
Pannu
Hariyadarshi
H
Department of Internal Medicine, Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, TX, USA.
Fadulu
Van Tran
VT
Chang
Jessica
J
Lafont
Andrea
A
Hasham
Sumera N
SN
Sparks
Elizabeth
E
Giampietro
Philip F
PF
Zaleski
Christina
C
Estrera
Anthony L
AL
Safi
Hazim J
HJ
Shete
Sanjay
S
Willing
Marcia C
MC
Raman
C S
CS
Milewicz
Dianna M
DM
D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000235:genetics*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II