Ziegler, A;
Duclaux-Loras, R;
Revenu, C;
Charbit-Henrion, F;
Begue, B;
Duroure, K;
Grimaud, L;
Guihot, AL;
Desquiret-Dumas, V;
Zarhrate, M;
et al.
Ziegler, A; Duclaux-Loras, R; Revenu, C; Charbit-Henrion, F; Begue, B; Duroure, K; Grimaud, L; Guihot, AL; Desquiret-Dumas, V; Zarhrate, M; Cagnard, N; Mas, E; Breton, A; Edouard, T; Billon, C; Frank, M; Colin, E; Lenaers, G; Henrion, D; Lyonnet, S; Faivre, L; Alembik, Y; Philippe, A; Moulin, B; Reinstein, E; Tzur, S; Attali, R; McGillivray, G; White, SM; Gallacher, L; Kutsche, K; Schneeberger, P; Girisha, KM; Nayak, SS; Pais, L; Maroofian, R; Rad, A; Vona, B; Karimiani, EG; Lekszas, C; Haaf, T; Martin, L; Ruemmele, F; Bonneau, D; Cerf-Bensussan, N; Del Bene, F; Parlato, M
(2021)
Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.
Am J Hum Genet, 108 (6).
pp. 1126-1137.
ISSN 1537-6605
https://doi.org/10.1016/j.ajhg.2021.04.020
SGUL Authors: Maroofian, Reza
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.
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