A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8
| Autor: | Abdulrahman Almesned, Dorien Schepers, Mehran Beiraghi Toosi, Zuhair N. Al-Hassnan, Jill A. Rosenfeld, Erin M. Miller, Hassan Mottaghi Moghaddam Shahri, Maaike Alaerts, Melanie Perik, Desiderio Rodrigues, Aline Verstraeten, Reza Maroofian, Silke Peeters, Cédric H. G. Neutel, Ilse Luyckx, Nicole Revencu, Jenny C. Taylor, Jarl Bastianen, Isabel Pintelon, Henry Houlden, Matteo P. Ferla, Erik Fransen, Kayal Vijayakumar, Lut Van Laer, Anthony R. Dallosso, Mandy Vermont, Isabelle Maystadt, Lotte Van Den Heuvel, Thierry Sluysmans, David Murphy, K. Nicole Weaver, Paria Najarzadeh Torbati, Jotte Rodrigues Bento, Amber Begtrup, Maggie Williams, Ilse Van Gucht, Maaike Bastiaansen, Ashish Chikermane, Gangadhara Bharmappanavara, Alistair T. Pagnamenta, Bart Loeys, Joe Davis Velchev, Julie Evans, Josephina A.N. Meester, Narges Hashemi, Julie Vogt, Pieter-Jan Guns |
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| Přispěvatelé: | Genomics England Res Consortium |
| Rok vydání: | 2021 |
| Předmět: |
Adult
Male 0301 basic medicine MMP2 Loss of Heterozygosity Importin 030204 cardiovascular system & hematology Biology Importin 8 Loeys–Dietz syndrome Thoracic aortic aneurysm Mice Young Adult 03 medical and health sciences All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine Loss of Function Mutation Transforming Growth Factor beta Report TGF beta signaling pathway Genetics medicine Animals Humans Child Genetics (clinical) Mice Knockout Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Aortic Aneurysm Thoracic Syndrome beta Karyopherins medicine.disease Pedigree Cell biology Mice Inbred C57BL CTGF Phenotype 030104 developmental biology Child Preschool Knockout mouse Female Human medicine Signal Transduction |
| Zdroj: | The American Journal of Human Genetics American Journal of Human Genetics, 108, 1115-1125 American Journal of Human Genetics, 108, 6, pp. 1115-1125 Am J Hum Genet The American journal of human genetics |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2021.04.019 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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