A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8

被引：12

作者：

Van Gucht, Ilse ^{[1
,2
]}

Meester, Josephina A. N. ^{[1
,2
]}

Bento, Jotte Rodrigues ^{[1
,2
]}

Bastiaansen, Maaike ^{[1
,2
]}

Bastianen, Jarl ^{[1
,2
]}

Luyckx, Ilse ^{[1
,2
,3
]}

Van den Heuvel, Lotte ^{[1
,2
]}

Neutel, Cedric H. G. ^{[4
]}

Guns, Pieter-Jan ^{[4
]}

Vermont, Mandy ^{[4
]}

Fransen, Erik ^{[1
,2
,5
]}

Perik, Melanie H. A. M. ^{[1
,2
]}

Velchev, Joe Davis ^{[1
,2
]}

Alaerts, Maaike ^{[1
,2
]}

Schepers, Dorien ^{[1
,2
,6
]}

Peeters, Silke ^{[1
,2
]}

Pintelon, Isabel ^{[7
]}

Almesned, Abdulrahman ^{[8
]}

Ferla, Matteo P. ^{[9
]}

Taylor, Jenny C. ^{[9
]}

Dallosso, Anthony R. ^{[10
]}

Williams, Maggie ^{[10
]}

Evans, Julie ^{[10
]}

Rosenfeld, Jill A. ^{[11
,12
]}

Sluysmans, Thierry ^{[13
]}

Rodrigues, Desiderio ^{[14
]}

Chikermane, Ashish ^{[15
]}

Bharmappanavara, Gangadhara ^{[16
]}

Vijayakumar, Kayal ^{[17
]}

Shahri, Hassan Mottaghi Moghaddam ^{[18
]}

Hashemi, Narges ^{[19
]}

Torbati, Paria Najarzadeh ^{[20
]}

Toosi, Mehran B. ^{[21
]}

Al-Hassnan, Zuhair N. ^{[22
]}

Vogt, Julie ^{[23
]}

Revencu, Nicole ^{[24
]}

Maystadt, Isabelle ^{[25
]}

Miller, Erin M. ^{[26
,27
]}

Weaver, K. Nicole ^{[27
,28
]}

Begtrup, Amber ^{[29
]}

Houlden, Henry ^{[30
]}

Murphy, David ^{[30
]}

Maroofian, Reza ^{[30
]}

Pagnamenta, Alistair T. ^{[9
]}

Van Laer, Lut ^{[1
,2
]}

Loeys, Bart L. ^{[1
,2
,3
]}

Verstraeten, Aline ^{[1
,2
]}

机构：

[1] Univ Antwerp, Ctr Med Genet, B-2650 Edegem, Belgium

[2] Antwerp Univ Hosp, B-2650 Edegem, Belgium

[3] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, NL-6525 GA Nijmegen, Netherlands

[4] Univ Antwerp, Lab Physiopharmacol, B-2610 Antwerp, Belgium

[5] Univ Antwerp, StatUa Ctr Stat, B-2000 Antwerp, Belgium

[6] Univ Antwerp, Lab Mol Cellular & Network Excitabil, Dept Biomed Sci, B-2610 Antwerp, Belgium

[7] Univ Antwerp, Dept Vet Sci, Lab Cell Biol & Histol, B-2610 Antwerp, Belgium

[8] Prince Sultan Cardiac Ctr, Qasim 31982, Saudi Arabia

[9] Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Ctr Human Genet, Oxford OX3 7BN, England

[10] Southmead Hosp, Bristol Genet Lab, South West Genom Lab Hub, Bristol BS10 5NB, Avon, England

[11] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77021 USA

[12] Baylor Genet Labs, Houston, TX 77021 USA

[13] Univ Louvain, Dept Pediat Cardiol, Clin Univ St Luc, B-1200 Brussels, Belgium

[14] Birmingham Womens & Childrens Hosp NHS Fdn Trust, Steelhouse Lane, Birmingham B4 6NH, W Midlands, England

[15] Birmingham Women & Childrens Hosp, Birmingham B4 6NH, W Midlands, England

[16] Somerset NHS Fdn Trust, Musgrove Pk Hosp, Taunton TA1 5DA, Somerset, England

[17] Univ Hosp Bristol NHS Fdn Trust, Dept Paediat Neurol, Bristol BS2 8BJ, Avon, England

[18] Mashhad Univ Med Sci, Fac Med, Pediat Dept, Mashhad 009851, Razavi Khorasan, Iran

[19] Mashhad Univ Med Sci, Sch Med, Dept Pediat Neurol, Mashhad 009851, Razavi Khorasan, Iran

[20] Mashhad Univ Med Sci, Dept Mol Genet, Next Generat Genet Polyclin, Mashhad 009851, Razavi Khorasan, Iran

[21] Mashhad Univ Med Sci, Ghaem Hosp, Dept Pediat Neurol, Mashhad 009851, Razavi Khorasan, Iran

[22] King Faisal Specialist Hosp & Res Ctr, Dept Med Genet, Cardiovasc Genet Program, Riyadh 11564, Saudi Arabia

[23] Birmingham Womens & Childrens Hosp, West Midlands Reg Genet Serv, Birmingham B15 2TG, W Midlands, England

[24] Univ Louvain, Ctr Human Genet, Clin Univ St Luc, B-1200 Brussels, Belgium

[25] Inst Pathol & Genet, Ctr Genet Humaine, B-6041 Gosselies, Charleroi, Belgium

[26] Cincinnati Childrens Hosp Med Ctr, Heart Inst, Dept Pediat, Cincinnati, OH 45229 USA

[27] Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA

[28] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Human Genet, Cincinnati, OH 45229 USA

[29] GeneDx, Gaithersburg, MD 20877 USA

[30] UCL Queen Sq Inst Neurol, Dept Neuromuscular Disorders, London WC1N 3BG, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2021年 / 108卷 / 06期

基金：

英国医学研究理事会; 英国惠康基金; 欧洲研究理事会;

关键词：

MUTATIONS; DISSECTIONS; INHIBITION; GROWTH; DOMAIN; ERK1/2; CTGF; SKI;

D O I：

10.1016/j.ajhg.2021.04.019

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-beta protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-beta signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm(TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8(-/-) mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-beta signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8(-/-) mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-beta signaling pathway in TAA development. Because importin 8 is the most downstream TGF-beta-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

引用

页码：1115 / 1125

页数：11

共 47 条

[1] A seX(X/Y) Article on Marfan Syndrome [J].

Anderson, Nicole K. ;

Juzwiak, Emily E. ;

Dietz, Harry C. .

JOURNAL OF THE AMERICAN HEART ASSOCIATION, 2020, 9 (20)

[2] Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome [J].

Bellini, C. ;

Korneva, A. ;

Zilberberg, L. ;

Ramirez, F. ;

Rifldn, D. B. ;

Humphrey, J. D. .

JOURNAL OF BIOMECHANICS, 2016, 49 (12) :2383-2389

[3] Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections [J].

Bertoli-Avella, Aida M. ;

Gillis, Elisabeth ;

Morisaki, Hiroko ;

Verhagen, Judith M. A. ;

de Graaf, Bianca M. ;

van de Beek, Gerarda ;

Gallo, Elena ;

Kruithof, Boudewijn P. T. ;

Venselaar, Hanka ;

Myers, Loretha A. ;

Laga, Steven ;

Doyle, Alexander J. ;

Oswald, Gretchen ;

van Cappellen, Gert W. A. ;

Yamanaka, Itaru ;

van der Helm, Robert M. ;

Beverloo, Berna ;

de Klein, Annelies ;

Pardo, Luba ;

Lammens, Martin ;

Evers, Christina ;

Devriendt, Koenraad ;

Dumoulein, Michiel ;

Timmermans, Janneke ;

Bruggenwirth, Hennie T. ;

Verheijen, Frans ;

Rodrigus, Inez ;

Baynam, Gareth ;

Kempers, Marlies ;

Saenen, Johan ;

Van Craenenbroeck, Emeline M. ;

Minatoya, Kenji ;

Matsukawa, Ritsu ;

Tsukube, Takuro ;

Kubo, Noriaki ;

Hofstra, Robert ;

Goumans, Marie Jose ;

Bekkers, Jos A. ;

Roos-Hesselink, Jolien W. ;

van de laar, Ingrid M. B. H. ;

Dietz, Harry C. ;

Van Laer, Lut ;

Morisaki, Takayuki ;

Wessels, Marja W. ;

Loeys, Bart L. .

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2015, 65 (13) :1324-1336

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

Boileau, Catherine ;

Guo, Dong-Chuan ;

Hanna, Nadine ;

Regalado, Ellen S. ;

Detaint, Delphine ;

Gong, Limin ;

Varret, Mathilde ;

Prakash, Siddharth K. ;

Li, Alexander H. ;

d'Indy, Hyacintha ;

Braverman, Alan C. ;

Grandchamp, Bernard ;

Kwartler, Callie S. ;

Gouya, Laurent ;

Santos-Cortez, Regie Lyn P. ;

Abifadel, Marianne ;

Leal, Suzanne M. ;

Muti, Christine ;

Shendure, Jay ;

Gross, Marie-Sylvie ;

Rieder, Mark J. ;

Vahanian, Alec ;

Nickerson, Deborah A. ;

Michel, Jean Baptiste ;

Jondeau, Guillaume ;

Milewicz, Dianna M. .

NATURE GENETICS, 2012, 44 (08) :916-+

[5] Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm [J].

Branchetti, Emanuela ;

Poggio, Paolo ;

Sainger, Rachana ;

Shang, Eric ;

Grau, Juan B. ;

Jackson, Benjamin M. ;

Lai, Eric K. ;

Parmacek, Michael S. ;

Gorman, Robert C. ;

Gorman, Joseph H. ;

Bavaria, Joseph E. ;

Ferrari, Giovanni .

CARDIOVASCULAR RESEARCH, 2013, 100 (02) :316-324

[6] Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype [J].

Cannaerts, Elyssa ;

Kempers, Marlies ;

Maugeri, Alessandra ;

Marcelis, Carlo ;

Gardeitchik, Thatjana ;

Richer, Julie ;

Micha, Dimitra ;

Beauchesne, Luc ;

Timmermans, Janneke ;

Vermeersch, Paul ;

Meyten, Nathalie ;

Chenier, Sebastien ;

van de Beek, Gerarda ;

Peeters, Nils ;

Alaerts, Maaike ;

Schepers, Dorien ;

Van Laer, Lut ;

Verstraeten, Aline ;

Loeys, Bart .

JOURNAL OF MEDICAL GENETICS, 2019, 56 (04) :220-227

[7] TGF-β signalopathies as a paradigm for translational medicine [J].

Cannaerts, Elyssa ;

van de Beek, Gerarda ;

Verstraeten, Aline ;

Van Laer, Lut ;

Loeys, Bart .

EUROPEAN JOURNAL OF MEDICAL GENETICS, 2015, 58 (12) :695-703

[8] Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting from the upregulated activities of matrix metalloproteinase-2 and-9 in the thoracic aortic aneurysm in Marfan syndrome [J].

Chung, Ada W. Y. ;

Yeung, Karen Au ;

Sandor, George G. S. ;

Judge, Daniel P. ;

Dietz, Harry C. ;

van Breemen, Cornelis .

CIRCULATION RESEARCH, 2007, 101 (05) :512-522

[9]

Dean KA, 2001, J CELL SCI, V114, P3479

[10] High-throughput discovery of novel developmental phenotypes [J].

Dickinson, Mary E. ;

Flenniken, Ann M. ;

Ji, Xiao ;

Teboul, Lydia ;

Wong, Michael D. ;

White, Jacqueline K. ;

Meehan, Terrence F. ;

Weninger, Wolfgang J. ;

Westerberg, Henrik ;

Adissu, Hibret ;

Baker, Candice N. ;

Bower, Lynette ;

Brown, James M. ;

Caddle, L. Brianna ;

Chiani, Francesco ;

Clary, Dave ;

Cleak, James ;

Daly, Mark J. ;

Denegre, James M. ;

Doe, Brendan ;

Dolan, Mary E. ;

Edie, Sarah M. ;

Fuchs, Helmut ;

Gailus-Durner, Valerie ;

Galli, Antonella ;

Gambadoro, Alessia ;

Gallegos, Juan ;

Guo, Shiying ;

Horner, Neil R. ;

Hsu, Chih-Wei ;

Johnson, Sara J. ;

Kalaga, Sowmya ;

Keith, Lance C. ;

Lanoue, Louise ;

Lawson, Thomas N. ;

Lek, Monkol ;

Mark, Manuel ;

Arschall, Susan M. ;

Mason, Jeremy ;

McElwee, Melissa L. ;

Newbigging, Susan ;

Nutter, Lauryl M. J. ;

Peterson, Kevin A. ;

Ramirez-Solis, Ramiro ;

Rowland, Douglas J. ;

Ryder, Edward ;

Samocha, Kaitlin E. ;

Seavitt, John R. ;

Selloum, Mohammed ;

Szoke-Kovacs, Zsombor .

NATURE, 2016, 537 (7621) :508-+

← 1 2 3 4 5 →