title: TGFβRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor β2 signal transduction.
abstract: BACKGROUND
  Thoracic aortic aneurysm (TAA) is a common progressive disorder involving gradual dilation of the ascending and/or descending thoracic aorta that eventually leads to dissection or rupture. Nonsydromic TAA can occur as a genetically triggered, familial disorder that is usually transmitted in a monogenic autosomal dominant fashion and is known as familial TAA. Genetic analyses of families affected with TAA have identified several chromosomal loci, and further mapping of familial TAA genes has highlighted disease-causing mutations in at least 4 genes: myosin heavy chain 11 (MYH11), α-smooth muscle actin (ACTA2), and transforming growth factor β receptors I and II (TGFβRI and TGFβRII).
  
  
  RESULTS
  We evaluated 100 probands to determine the mutation frequency in MYH11, ACTA2, TGFβRI, and TGFβRII in an unbiased population of individuals with genetically mediated TAA. In this study, 9% of patients had a mutation in one of the genes analyzed, 3% of patients had mutations in ACTA2, 3% in MYH11, 1% in TGFβRII, and no mutations were found in TGFβRI. Additionally, we identified mutations in a 75 base pair alternatively spliced TGFβRII exon, exon 1a that produces the TGFβRIIb isoform and accounted for 2% of patients with mutations. Our in vitro analyses indicate that the TGFβRIIb activating mutations alter receptor function on TGFβ2 signaling.
  
  
  CONCLUSIONS
  We propose that TGFβRIIb expression is a regulatory mechanism for TGFβ2 signal transduction. Dysregulation of the TGFβ2 signaling pathway, as a consequence of TGFβRIIb mutations, results in aortic aneurysm pathogenesis.
authors.affiliation: Center for Molecular Cardiology, Greenberg Division of Cardiology, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Bee
authors.forename: David C
authors.initials: DC
authors.lastname: Wilkes
authors.forename: Richard B
authors.initials: RB
authors.lastname: Devereux
authors.forename: Craig T
authors.initials: CT
authors.lastname: Basson
authors.forename: Cathy J
authors.initials: CJ
authors.lastname: Hatcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D053781:Transforming Growth Factor beta2 / Q000378:metabolism* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018995:Myosin Heavy Chains