Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 6, Pages 1126-1137Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2021.04.020
Keywords
-
Categories
Funding
- Agence Nationale de la Recherche [ANR-10-IAHU-01]
- INSERM
- Fondation Princesse Grace
- Fondation Maladies Rares
- CNRS
- University of Angers
- University of Tubingen [2545-1-0]
- Ministry of Science, Research and Art Baden-Wurttemberg
- Programme Investissements d'Avenir IHU FOReSIGHT [ANR-18-IAHU-01]
- EU [661527]
- Indian Council of Medical Research [5/7/1508/2016]
- Federal Ministry of Education and Research [01DQ17003]
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung, and Blood Institute [UM1 HG008900]
- National Human Genome Research Institute [R01 HG009141]
- Murdoch Children's Research Institute
- Victorian Government
- Harbig Family Foundation
- Royal Children's Hospital Foundation
- [ERC-2013-AdG-339407-IMMUNOBIOTA]
- Marie Curie Actions (MSCA) [661527] Funding Source: Marie Curie Actions (MSCA)
Ask authors/readers for more resources
This study identified bi-allelic loss-of-function variants in the IPO8 gene in 12 individuals with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, dysmorphic features, and developmental delay. Functional studies in zebrafish demonstrated the critical role of IPO8 in TGF-beta signaling during development, linking it to connective tissue defects.
Dysregulated transforming growth factor TGF-beta 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-beta-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-beta 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-beta signaling during development and reinforces the existing link between TGF-beta signaling and connective tissue defects.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available