4.7 Article

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

期刊

AMERICAN JOURNAL OF HUMAN GENETICS
卷 108, 期 6, 页码 1115-1125

出版社

CELL PRESS
DOI: 10.1016/j.ajhg.2021.04.019

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资金

  1. University of Antwerp [FFB190208, 30706]
  2. Research Foundation Flanders (FWO, Belgium) [G042321N, G040221N, G044720N]
  3. Dutch Heart Foundation [2013T093]
  4. Belgian Cardiac Surgery Foundation
  5. Marfan Foundation
  6. National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford
  7. Wellcome Trust [203141/Z/16/Z]
  8. National Institute for Health Research
  9. NHS England
  10. Wellcome Trust
  11. Cancer Research UK
  12. Medical Research Council
  13. European Research Council [Genomia-ERC-COG-2017-771945]
  14. FWO [12X8520N, 12R5610N]
  15. FWO PhD fellowship [1S70419N, 1S81820N, 11C1721N, 1S24 720N]
  16. European Union Third Health Programme [769036]

向作者/读者索取更多资源

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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