OBJECTIVE: Mutations in FBN1 and TGFBR2 genes are the main causative mutations identified in Marfan syndrome (MFS). The major vascular complication of MFS is aneurysm formation. Abdominal aortic aneurysm (AAA) is an acquired disease of later life of unknown etiology. The aim of this study was to examine if genetic aberrations in MFS-related genes FBN1 and TGFBR2 are present in patients with AAA. METHODS: We assessed the presence of copy number variation (CNV) in FBN1 and TGFBR2 genes in AAA biopsies from twelve patients. We also analyzed the expression of these genes in AAA biopsies compared to control biopsies from six organ donors. In addition we assessed the expression of two members of the Notch signaling pathway NOTCH3 and HEY2 as well as aortic smooth muscle cell (AoSMC) differentiation marker TAGLN in AAA and control biopsies. RESULTS: Loss of one copy (deletion) of the FBN1 exon 66 sequence and TGFBR2 exon 8 was identified in 7 (58%) and 11 (92%) of the 12 AAA biopsies. No copy number amplifications (duplications) were detected. Patients carrying TGFBR2 exon 8 deletion showed marked downregulation of this gene in AAA biopsies compared to control biopsies (0.699 vs. 1.765, p = 0.038). Notch signaling components NOTCH3 and HEY2 were markedly downregulated in AAA, while expression of the AoSMC differentiation marker TAGLN did not differ between AAA and control biopsies (0.468 vs. 0.486, p = 0.546). CONCLUSION: This study suggests an acquired impairment in TGF-β signaling that along with downregulation of the Notch signaling pathway may contribute to the pathogenesis of AAA.
OBJECTIVE: Mutations in FBN1 and TGFBR2 genes are the main causative mutations identified in Marfan syndrome (MFS). The major vascular complication of MFS is aneurysm formation. Abdominal aortic aneurysm (AAA) is an acquired disease of later life of unknown etiology. The aim of this study was to examine if genetic aberrations in MFS-related genes FBN1 and TGFBR2 are present in patients with AAA. METHODS: We assessed the presence of copy number variation (CNV) in FBN1 and TGFBR2 genes in AAA biopsies from twelve patients. We also analyzed the expression of these genes in AAA biopsies compared to control biopsies from six organ donors. In addition we assessed the expression of two members of the Notch signaling pathway NOTCH3 and HEY2 as well as aortic smooth muscle cell (AoSMC) differentiation marker TAGLN in AAA and control biopsies. RESULTS: Loss of one copy (deletion) of the FBN1 exon 66 sequence and TGFBR2 exon 8 was identified in 7 (58%) and 11 (92%) of the 12 AAA biopsies. No copy number amplifications (duplications) were detected. Patients carrying TGFBR2 exon 8 deletion showed marked downregulation of this gene in AAA biopsies compared to control biopsies (0.699 vs. 1.765, p = 0.038). Notch signaling components NOTCH3 and HEY2 were markedly downregulated in AAA, while expression of the AoSMC differentiation marker TAGLN did not differ between AAA and control biopsies (0.468 vs. 0.486, p = 0.546). CONCLUSION: This study suggests an acquired impairment in TGF-β signaling that along with downregulation of the Notch signaling pathway may contribute to the pathogenesis of AAA.
Authors: Adam J Doyle; Eileen M Redmond; David L Gillespie; Peter A Knight; John P Cullen; Paul A Cahill; David J Morrow Journal: J Vasc Surg Date: 2014-04-24 Impact factor: 4.268
Authors: Corey S Moran; Erik Biros; Smriti M Krishna; Susan K Morton; Daniel J Sexton; Jonathan Golledge Journal: J Am Heart Assoc Date: 2021-02-18 Impact factor: 5.501
Authors: Lars Maegdefessel; Joshua M Spin; Matti Adam; Uwe Raaz; Ryuji Toh; Futoshi Nakagami; Philip S Tsao Journal: Int J Mol Sci Date: 2013-07-11 Impact factor: 5.923
Authors: Joshua E Basford; Sheryl Koch; Ahmad Anjak; Vivek P Singh; Eric G Krause; Nathan Robbins; Neal L Weintraub; David Y Hui; Jack Rubinstein Journal: PLoS One Date: 2013-11-29 Impact factor: 3.240
Authors: Verneri Anttila; Bendik S Winsvold; Padhraig Gormley; Tobias Kurth; Francesco Bettella; George McMahon; Mikko Kallela; Rainer Malik; Boukje de Vries; Gisela Terwindt; Sarah E Medland; Unda Todt; Wendy L McArdle; Lydia Quaye; Markku Koiranen; M Arfan Ikram; Terho Lehtimäki; Anine H Stam; Lannie Ligthart; Juho Wedenoja; Ian Dunham; Benjamin M Neale; Priit Palta; Eija Hamalainen; Markus Schürks; Lynda M Rose; Julie E Buring; Paul M Ridker; Stacy Steinberg; Hreinn Stefansson; Finnbogi Jakobsson; Debbie A Lawlor; David M Evans; Susan M Ring; Markus Färkkilä; Ville Artto; Mari A Kaunisto; Tobias Freilinger; Jean Schoenen; Rune R Frants; Nadine Pelzer; Claudia M Weller; Ronald Zielman; Andrew C Heath; Pamela A F Madden; Grant W Montgomery; Nicholas G Martin; Guntram Borck; Hartmut Göbel; Axel Heinze; Katja Heinze-Kuhn; Frances M K Williams; Anna-Liisa Hartikainen; Anneli Pouta; Joyce van den Ende; Andre G Uitterlinden; Albert Hofman; Najaf Amin; Jouke-Jan Hottenga; Jacqueline M Vink; Kauko Heikkilä; Michael Alexander; Bertram Muller-Myhsok; Stefan Schreiber; Thomas Meitinger; Heinz Erich Wichmann; Arpo Aromaa; Johan G Eriksson; Bryan Traynor; Daniah Trabzuni; Elizabeth Rossin; Kasper Lage; Suzanne B R Jacobs; J Raphael Gibbs; Ewan Birney; Jaakko Kaprio; Brenda W Penninx; Dorret I Boomsma; Cornelia van Duijn; Olli Raitakari; Marjo-Riitta Jarvelin; John-Anker Zwart; Lynn Cherkas; David P Strachan; Christian Kubisch; Michel D Ferrari; Arn M J M van den Maagdenberg; Martin Dichgans; Maija Wessman; George Davey Smith; Kari Stefansson; Mark J Daly; Dale R Nyholt; Daniel Chasman; Aarno Palotie Journal: Nat Genet Date: 2013-06-23 Impact factor: 38.330