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Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation

Abstract : 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.
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https://hal.inrae.fr/hal-03318994
Contributor : Nathalie Seguin <>
Submitted on : Wednesday, August 11, 2021 - 3:05:56 PM
Last modification on : Saturday, August 14, 2021 - 3:28:12 AM

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Alban Ziegler, Rémi Duclaux-Loras, Céline Revenu, Fabienne Charbit-Henrion, Bernadette Begue, et al.. Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation. American Journal of Human Genetics, Elsevier (Cell Press), 2021, 108 (6), pp.1126-1137. ⟨10.1016/j.ajhg.2021.04.020⟩. ⟨hal-03318994⟩

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