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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.

Original publication

DOI

10.1016/j.ajhg.2021.04.019

Type

Journal article

Journal

American journal of human genetics

Publication Date

06/2021

Volume

108

Pages

1115 - 1125

Addresses

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem 2650, Belgium.

Keywords

Genomics England Research Consortium, Animals, Mice, Inbred C57BL, Mice, Knockout, Humans, Mice, Aortic Aneurysm, Thoracic, Syndrome, Transforming Growth Factor beta, beta Karyopherins, Pedigree, Signal Transduction, Phenotype, Loss of Heterozygosity, Adult, Child, Child, Preschool, Female, Male, Young Adult, Loss of Function Mutation