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.
Original language | English |
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Pages (from-to) | 1126-1137 |
Number of pages | 12 |
Journal | American Journal of Human Genetics |
Volume | 108 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 3 2021 |
Keywords
- IPO8
- Loeys-Dietz syndrome
- TGF-β signaling
- arterial dilatation
- connective tissue disorder
- joint hyperlaxity
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)