Ziegler, Alban;
Duclaux-Loras, Remi;
Revenu, Celine;
Charbit-Henrion, Fabienne;
Begue, Bernadette;
Duroure, Karine;
Grimaud, Linda;
... Parlato, Marianna; + view all
(2021)
Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.
American Journal of Human Genetics
, 108
(6)
pp. 1126-1137.
10.1016/j.ajhg.2021.04.020.
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Abstract
Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-β-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-β signaling, ipo8−/− zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8−/− zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-β signaling during development and reinforces the existing link between TGF-β signaling and connective tissue defects.
| Type: | Article |
|---|---|
| Title: | Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajhg.2021.04.020 |
| Publisher version: | https://doi.org/10.1016/j.ajhg.2021.04.020 |
| Language: | English |
| Additional information: | © 2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, INFLAMMATORY-BOWEL-DISEASE, NUCLEAR IMPORT, MUTATIONS, GENES, ZEBRAFISH |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10146455 |
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