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

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

Edité par CCSD ; Elsevier (Cell Press) -

International audience. 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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