title: TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.
abstract: A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
authors: Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat, Paris, France. catherine.boileau@inserm.fr
authors: Catherine
authors: C
authors: Boileau
authors: Dong-Chuan
authors: DC
authors: Guo
authors: Nadine
authors: N
authors: Hanna
authors: Ellen S
authors: ES
authors: Regalado
authors: Delphine
authors: D
authors: Detaint
authors: Limin
authors: L
authors: Gong
authors: Mathilde
authors: M
authors: Varret
authors: Siddharth K
authors: SK
authors: Prakash
authors: Alexander H
authors: AH
authors: Li
authors: Hyacintha
authors: H
authors: d'Indy
authors: Alan C
authors: AC
authors: Braverman
authors: Bernard
authors: B
authors: Grandchamp
authors: Callie S
authors: CS
authors: Kwartler
authors: Laurent
authors: L
authors: Gouya
authors: Regie Lyn P
authors: RL
authors: Santos-Cortez
authors: Marianne
authors: M
authors: Abifadel
authors: Suzanne M
authors: SM
authors: Leal
authors: Christine
authors: C
authors: Muti
authors: Jay
authors: J
authors: Shendure
authors: Marie-Sylvie
authors: MS
authors: Gross
authors: Mark J
authors: MJ
authors: Rieder
authors: Alec
authors: A
authors: Vahanian
authors: Deborah A
authors: DA
authors: Nickerson
authors: Jean Baptiste
authors: JB
authors: Michel
authors: Guillaume
authors: G
authors: Jondeau
authors: Dianna M
authors: DM
authors: Milewicz
mesh_terms: D000784:Aortic Dissection / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018389:Codon, Nonsense; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057895:Haploinsufficiency; D006801:Humans; D008126:Lod Score; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D053781:Transforming Growth Factor beta2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2