Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 6, Pages 1115-1125Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2021.04.019
Keywords
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Categories
Funding
- University of Antwerp [FFB190208, 30706]
- Research Foundation Flanders (FWO, Belgium) [G042321N, G040221N, G044720N]
- Dutch Heart Foundation [2013T093]
- Belgian Cardiac Surgery Foundation
- Marfan Foundation
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford
- Wellcome Trust [203141/Z/16/Z]
- National Institute for Health Research
- NHS England
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- European Research Council [Genomia-ERC-COG-2017-771945]
- FWO [12X8520N, 12R5610N]
- FWO PhD fellowship [1S70419N, 1S81820N, 11C1721N, 1S24 720N]
- European Union Third Health Programme [769036]
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Importin 8, encoded by IPO8, is crucial for the development of thoracic aortic aneurysm (TAA) and its loss-of-function variants may cause a syndromic form of TAA with clinical overlap with other syndromes. Importin 8 plays a role in dysregulation of the TGF-beta signaling pathway, providing potential for future mechanistic studies and drug targeting in TAA.
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.
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