PUBLICATION

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

Authors
Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A.L., 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, S.M., Gallacher, L., Kutsche, K., Schneeberger, P., Girisha, K.M., Nayak, S.S., Pais, L., Maroofian, R., Rad, A., Vona, B., Karimiani, E.G., Lekszas, C., Haaf, T., Martin, L., Ruemmele, F., Bonneau, D., Cerf-Bensussan, N., Del Bene, F., Parlato, M.
ID
ZDB-PUB-210520-9
Date
2021
Source
American journal of human genetics   108(6): 1126-1137 (Other)
Registered Authors
Del Bene, Filippo, Revenu, Celine
Keywords
IPO8, Loeys-Dietz syndrome, TGF-β signaling, arterial dilatation, connective tissue disorder, joint hyperlaxity
MeSH Terms
  • Adolescent
  • Adult
  • Animals
  • Bone Diseases/etiology*
  • Bone Diseases/pathology
  • Cardiovascular Diseases/etiology*
  • Cardiovascular Diseases/pathology
  • Child
  • Connective Tissue Diseases/etiology*
  • Connective Tissue Diseases/pathology
  • Female
  • Humans
  • Immunity, Cellular/immunology*
  • Infant
  • Loss of Function Mutation*
  • Loss of Heterozygosity*
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Signal Transduction
  • Transforming Growth Factor beta/genetics
  • Transforming Growth Factor beta/metabolism
  • Young Adult
  • Zebrafish
  • beta Karyopherins/genetics*
  • beta Karyopherins/metabolism
PubMed
34010604 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping