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
-
- Bone Diseases/etiology*
- Bone Diseases/pathology
- Middle Aged
- Young Adult
- Loss of Function Mutation*
- Child
- Connective Tissue Diseases/etiology*
- Connective Tissue Diseases/pathology
- Female
- Infant
- Zebrafish
- Animals
- Adolescent
- Phenotype
- Signal Transduction
- Humans
- Cardiovascular Diseases/etiology*
- Cardiovascular Diseases/pathology
- Immunity, Cellular/immunology*
- Pedigree
- Loss of Heterozygosity*
- Male
- Adult
- Transforming Growth Factor beta/genetics
- Transforming Growth Factor beta/metabolism
- beta Karyopherins/genetics*
- beta Karyopherins/metabolism
- PubMed
- 34010604 Full text @ Am. J. Hum. Genet.
Citation
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. (2021) Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation. American journal of human genetics. 108(6):1126-1137.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping