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Nat Genet. 2012 Jul 8;44(8):916-21. doi: 10.1038/ng.2348.

TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.

Collaborators (388)

Gabriel SB, Altshuler DM, Abecasis GR, Allayee H, Cresci S, Daly MJ, de Bakker PI, Depristo MA, Do R, Donnelly P, Farlow DN, Fennell T, Garimella K, Hazen SL, Hu Y, Jordan DM, Jun G, Kathiresan S, Kang HM, Kiezun A, Lettre G, Li B, Li M, Newton-Cheh CH, Padmanabhan S, Peloso G, Pulit S, Rader DJ, Reich D, Reilly MP, Rivas MA, Schwartz S, Scott L, Siscovick DS, Spertus JA, Stitziel NO, Stoletzki N, Sunyaev SR, Voight BF, Willer CJ, Rich SS, Akylbekova E, Atwood LD, Ballantyne CM, Barbalic M, Barr RG, Benjamin EJ, Bis J, Boerwinkle E, Bowden DW, Brody J, Budoff M, Burke G, Buxbaum S, Carr J, Chen DT, Chen IY, Chen WM, Concannon P, Crosby J, Cupples L, D'Agostino R, DeStefano AL, Dreisbach A, Dupuis J, Durda J, Ellis J, Folsom AR, Fornage M, Fox CS, Fox E, Funari V, Ganesh SK, Gardin J, Goff D, Gordon O, Grody W, Gross M, Guo X, Hall IM, Heard-Costa NL, Heckbert SR, Heintz N, Herrington DM, Hickson D, Huang J, Hwang SJ, Jacobs DR, Jenny NS, Johnson AD, Johnson CW, Kawut S, Kronmal R, Kurz R, Lange EM, Lange LA, Larson MG, Lawson M, Lewis CE, Levy D, Li D, Lin H, Liu C, Liu J, Liu K, Liu X, Liu Y, Longstreth WT, Loria C, Lumley T, Lunetta K, Mackey AJ, Mackey R, Manichaikul A, Maxwell T, McKnight B, Meigs JB, Morrison AC, Musani SK, Mychaleckyj JC, Nettleton JA, North K, O'Donnell CJ, O'Leary D, Ong F, Palmas W, Pankow JS, Pankratz ND, Paul S, Perez M, Person SD, Polak J, Post WS, Psaty BM, Quinlan AR, Raffel LJ, Ramachandran VS, Reiner AP, Rice K, Rotter JI, Sanders JP, Schreiner P, Seshadri S, Shea S, Sidney S, Silverstein K, Siscovick DS, Smith NL, Sotoodehnia N, Srinivasan A, Taylor HA, Taylor K, Thomas F, Tracy RP, Tsai MY, Volcik KA, Wassel CL, Watson K, Wei G, White W, Wiggins KL, Wilk JB, Williams O, Wilson G, Wilson JG, Wolf P, Zakai NA, Hardy J, Meschia JF, Nalls M, Rich SS, Singleton A, Worrall B, Bamshad MJ, Barnes KC, Abdulhamid I, Accurso F, Beaty T, Bigham A, Black P, Bleecker E, Buckingham K, Cairns AM, Chen WM, Caplan D, Chatfield B, Chidekel A, Cho M, Christiani DC, Crapo JD, Crouch J, Daley D, Dang A, Dang H, De Paula A, DeCelie-Germana J, Dozor A, Drumm M, Dyson M, Emerson J, Emond MJ, Ferkol T, Fink R, Foster C, Froh D, Gao L, Gershan W, Gibson RL, Godwin E, Gondor M, Gutierrez H, Hansel NN, Hassoun PM, Hiatt P, Hokanson JE, Howenstine M, Hummer LK, Kanga J, Kim Y, Knowles MR, Konstan M, Lahiri T, Laird N, Lange C, Lin L, Lin X, Louie TL, Lynch D, Make B, Martin TR, Mathai SC, Mathias RA, McNamara J, McNamara S, Meyers D, Millard S, Mogayzel P, Moss R, Murray T, Nielson D, Noyes B, O'Neal W, Orenstein D, O'Sullivan B, Pace R, Pare P, Parker H, Passero MA, Perkett E, Prestridge A, Rafaels NM, Ramsey B, Regan E, Ren C, Retsch-Bogart G, Rock M, Rosen A, Rosenfeld M, Ruczinski I, Sanford A, Schaeffer D, Sell C, Sheehan D, Silverman EK, Sin D, Spencer T, Stonebraker J, Tabor HK, Varlotta L, Vergara CI, Weiss R, Wigley F, Wise RA, Wright FA, Wurfel MM, Zanni R, Zou F, Nickerson DA, Rieder MJ, Green P, Shendure J, Akey JM, Bamshad MJ, Bustamante CD, Crosslin DR, Eichler EE, Fox P, Gordon A, Gravel S, Jarvik GP, Johnsen JM, Kan M, Kenny EE, Kidd JM, Lara-Garduno F, Leal SM, Liu DJ, McGee S, Paeper B, Robertson PD, Smith JD, Turner EH, Wang G, Jackson R, North K, Peters U, Carlson CS, Anderson G, Anton-Culver H, Assimes TL, Auer PL, Beresford S, Bizon C, Black H, Brunner R, Brzyski R, Burwen D, Caan B, Carty CL, Chlebowski R, Cummings S, Curb J, Eaton CB, Ford L, Franceschini N, Fullerton SM, Gass M, Geller N, Heiss G, Howard BV, Hsu L, Hutter CM, Ioannidis J, Jiao S, Johnson KC, Kooperberg C, Kuller L, LaCroix A, Lakshminarayan K, Lane D, Lange EM, Lange LA, Lasser N, LeBlanc E, Lewis CE, Li KP, Limacher M, Lin DY, Logsdon BA, Ludlam S, Manson JE, Margolis K, Martin L, McGowan J, Monda KL, Kotchen JM, Nathan L, Ockene J, O'Sullivan MJ, Phillips LS, Prentice RL, Reiner AP, Robbins J, Robinson JG, Rossouw JE, Sangi-Haghpeykar H, Sarto GE, Shumaker S, Simon MS, Stefanick ML, Stein E, Tang H, Taylor KC, Thomson CA, Thornton TA, Van Horn L, Vitolins M, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Zeng D, Applebaum-Bowden D, Feolo M, Gan W, Paltoo DN, Rossouw JE, Sholinsky P, Sturcke A.

Author information

1
Institut National de la Santé et de la Recherche Médicale (INSERM) U698, Hôpital Bichat, Paris, France. catherine.boileau@inserm.fr

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.

PMID:
22772371
PMCID:
PMC4033668
DOI:
10.1038/ng.2348
[Indexed for MEDLINE]
Free PMC Article

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