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

• DOI: 10.1016/j.ajhg.2021.04.020
• Publication Date: 2021-05-18T15:18:01Z
• Authors: Alban Ziegler; Rémi Duclaux-Loras; Céline Revenu; Fabienne Charbit-...; Bernadette Begue; Karine Duroure; Linda Grimaud; Anne Laure Guihot; Valérie Desquiret...; Mohammed Zarhrate; Nicolas Cagnard; Emmanuel Mas; Anne Breton; Thomas Edouard; Clarisse Billon; Michael Frank; Estelle Colin; Guy Lenaers; Daniel Henrion; Stanislas Lyonnet; Laurence 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 Kar...; Caroline Lekszas; Thomas Haaf; Ludovic Martin; Frank Ruemmele; Dominique Bonneau; Nadine Cerf-Bensu...; Filippo Del Bene; Marianna Parlato
• Keywords: Immune Dysregulation; Connective Tissue Disorder

Dysregulated transforming growth factor TGF-β signaling underlies the pathogenesis of genetic disorders affecting connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree dysmorphic features developmental delay well immune dysregulation; were from nine unrelated families. Importin 8 belongs to karyopherin family nuclear transport receptors was previously shown mediate TGF-β-dependent SMADs trafficking nucleus vitro. The important vivo role pSMAD translocation demonstrated CRISPR/Cas9-mediated inactivation zebrafish. Consistent IPO8's BMP/TGF-β signaling, ipo8−/− zebrafish mild severe dorso-ventral patterning defects during early embryonic development. Moreover, displayed cardiovascular skeletal that mirrored human phenotype. Our work thus provides evidence plays critical non-redundant development reinforces existing link between defects.