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

Alban Ziegler, Rémi Duclaux-Loras, Céline Revenu, Fabienne Charbit-Henrion, Bernadette Begue, Karine Duroure, Linda Grimaud, Anne Laure Guihot, Valérie Desquiret-Dumas, Mohammed Zarhrate, Nicolas Cagnard, Emmanuel Mas, Anne Breton, Thomas Edouard, Clarisse Billon, Michael Frank, Estelle Colin, Guy Lenaers, Daniel Henrion, Stanislas LyonnetLaurence Faivre, Yves Alembik, Anaïs Philippe, Bruno Moulin, Eyal Reinstein, Shay Tzur, Ruben Attali, George McGillivray, Susan M. White, Lyndon Gallacher, Kerstin Kutsche, Pauline Schneeberger, Katta M. Girisha, Shalini S. Nayak, Lynn Pais, Reza Maroofian, Aboulfazl Rad, Barbara Vona, Ehsan Ghayoor Karimiani, Caroline Lekszas, Thomas Haaf, Ludovic Martin, Frank Ruemmele, Dominique Bonneau, Nadine Cerf-Bensussan, Filippo Del Bene, Marianna Parlato

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


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 languageEnglish
Pages (from-to)1126-1137
Number of pages12
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - 03-06-2021

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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