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

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