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

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-β 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-β 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-β 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-β signaling pathway in TAA development. Because importin 8 is the most downstream TGF-β-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA. Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

Ilse Van Gucht, Josephina A N Meester, Jotte Rodrigues Bento, Maaike Bastiaansen, Jarl Bastianen, Ilse Luyckx, Lotte Van Den Heuvel, Cédric H G Neutel, Pieter-Jan Guns, Mandy Vermont, Erik Fransen, Melanie H A M Perik, Joe Davis Velchev, Maaike Alaerts, Dorien Schepers, Silke Peeters, Isabel Pintelon, Abdulrahman Almesned, Matteo P Ferla, Jenny C Taylor, Anthony R Dallosso, Maggie Williams, Julie Evans, Genomics England Research Consortium, Jill A Rosenfeld, Thierry Sluysmans, Desiderio Rodrigues, Ashish Chikermane, Gangadhara Bharmappanavara, Kayal Vijayakumar, Hassan Mottaghi Moghaddam Shahri, Narges Hashemi, Paria Najarzadeh Torbati, Mehran B Toosi, Zuhair N Al-Hassnan, Julie Vogt, Nicole Revencu, Isabelle Maystadt, Erin M Miller, K Nicole Weaver, Amber Begtrup, Henry Houlden, David Murphy, Reza Maroofian, Alistair T Pagnamenta, Lut Van Laer, Bart L Loeys, Aline Verstraeten. A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. American journal of human genetics. 2021 Jun 03;108(6):1115-1125

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PMID: 34010605

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