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

Alban Ziegler; Rémi Duclaux-Loras; Céline Revenu; Fabienne Charbit-Henrion; Bernadette Begue; Karine Duroure; Linda Grimaud; Anne Laure Guihot; Valérie Desquiret-Dumas; 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 Karimiani; Caroline Lekszas; Thomas Haaf; Ludovic Martin; Frank Ruemmele; Dominique Bonneau; Nadine Cerf-Bensussan; Filippo Del Bene; Marianna Parlato

doi:10.1016/j.ajhg.2021.04.020

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

Alban Ziegler, Rémi Duclaux-Loras, Céline Revenu, Fabienne Charbit-Henrion, Bernadette Begue, Karine Duroure, Linda Grimaud, Anne Laure Guihot, Valérie Desquiret-Dumas, Mohammed Zarhrate, Nicolas Cagnard, Emmanuel Mas, Anne Breton, Thomas Edouard, Clarisse Billon, Michael Frank, Estelle Colin, Guy Lenaers, Daniel Henrion, Stanislas LyonnetLaurence 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 Karimiani, Caroline Lekszas, Thomas Haaf, Ludovic Martin, Frank Ruemmele, Dominique Bonneau, Nadine Cerf-Bensussan, Filippo Del Bene^*, Marianna Parlato^*

^*Corresponding author for this work

Internal Medicine

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Pages (from-to)	1126-1137
Number of pages	12
Journal	American Journal of Human Genetics
Volume	108
Issue number	6
DOIs	https://doi.org/10.1016/j.ajhg.2021.04.020
State	Published - 3 Jun 2021

Funding

Funders	Funder number
Fondation Princesse Grace
Broad Institute
Murdoch Children's Research Institute
Universite Angers
Royal Children's Hospital Foundation
Centre National de la Recherche Scientifique
State Government of Victoria
European Commission
Fondation Maladies Rares
National Heart, Lung, and Blood Institute
Harbig Family Foundation
Harvard Center for Mendelian Genomics
National Eye Institute
EU Horizon 2020 Marie Skłodowska-Curie Action
National Human Genome Research Institute	R01HG009141, UM1HG008900
Indian Council of Medical Research	5/7/1508/2016
Horizon 2020 Framework Programme	339407
Seventh Framework Programme	661527
Institut national de la santé et de la recherche médicale	ERC-2013-AdG-339407-IMMUNOBIOTA
Eberhard Karls Universität Tübingen	2545-1-0
Bundesministerium für Bildung und Forschung	01DQ17003
Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg	ANR-18-IAHU-01
Agence Nationale de la Recherche	ANR-10-IAHU-01

Keywords

IPO8
Loeys-Dietz syndrome
TGF-β signaling
arterial dilatation
connective tissue disorder
joint hyperlaxity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2021.04.020

Cite this

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., ... 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. https://doi.org/10.1016/j.ajhg.2021.04.020

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

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.",

keywords = "IPO8, Loeys-Dietz syndrome, TGF-β signaling, arterial dilatation, connective tissue disorder, joint hyperlaxity",

author = "Alban Ziegler and R{\'e}mi Duclaux-Loras and C{\'e}line Revenu and Fabienne Charbit-Henrion and Bernadette Begue and Karine Duroure and Linda Grimaud and Guihot, {Anne Laure} and Val{\'e}rie Desquiret-Dumas and Mohammed Zarhrate and Nicolas Cagnard and Emmanuel Mas and Anne Breton and Thomas Edouard and Clarisse Billon and Michael Frank and Estelle Colin and Guy Lenaers and Daniel Henrion and Stanislas Lyonnet and Laurence Faivre and Yves Alembik and Ana{\"i}s Philippe and Bruno Moulin and Eyal Reinstein and Shay Tzur and Ruben Attali and George McGillivray and White, {Susan M.} and Lyndon Gallacher and Kerstin Kutsche and Pauline Schneeberger and Girisha, {Katta M.} and Nayak, {Shalini S.} and Lynn Pais and Reza Maroofian and Aboulfazl Rad and Barbara Vona and Karimiani, {Ehsan Ghayoor} and Caroline Lekszas and Thomas Haaf and Ludovic Martin and Frank Ruemmele and Dominique Bonneau and Nadine Cerf-Bensussan and {Del Bene}, Filippo and Marianna Parlato",

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doi = "10.1016/j.ajhg.2021.04.020",

language = "אנגלית",

volume = "108",

pages = "1126--1137",

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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', American Journal of Human Genetics, vol. 108, no. 6, pp. 1126-1137. https://doi.org/10.1016/j.ajhg.2021.04.020

TY - JOUR

T1 - Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation

AU - Ziegler, Alban

AU - Duclaux-Loras, Rémi

AU - Revenu, Céline

AU - Charbit-Henrion, Fabienne

AU - Begue, Bernadette

AU - Duroure, Karine

AU - Grimaud, Linda

AU - Guihot, Anne Laure

AU - Desquiret-Dumas, Valérie

AU - Zarhrate, Mohammed

AU - Cagnard, Nicolas

AU - Mas, Emmanuel

AU - Breton, Anne

AU - Edouard, Thomas

AU - Billon, Clarisse

AU - Frank, Michael

AU - Colin, Estelle

AU - Lenaers, Guy

AU - Henrion, Daniel

AU - Lyonnet, Stanislas

AU - Faivre, Laurence

AU - Alembik, Yves

AU - Philippe, Anaïs

AU - Moulin, Bruno

AU - Reinstein, Eyal

AU - Tzur, Shay

AU - Attali, Ruben

AU - McGillivray, George

AU - White, Susan M.

AU - Gallacher, Lyndon

AU - Kutsche, Kerstin

AU - Schneeberger, Pauline

AU - Girisha, Katta M.

AU - Nayak, Shalini S.

AU - Pais, Lynn

AU - Maroofian, Reza

AU - Rad, Aboulfazl

AU - Vona, Barbara

AU - Karimiani, Ehsan Ghayoor

AU - Lekszas, Caroline

AU - Haaf, Thomas

AU - Martin, Ludovic

AU - Ruemmele, Frank

AU - Bonneau, Dominique

AU - Cerf-Bensussan, Nadine

AU - Del Bene, Filippo

AU - Parlato, Marianna

PY - 2021/6/3

Y1 - 2021/6/3

N2 - 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.

AB - 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.

KW - IPO8

KW - Loeys-Dietz syndrome

KW - TGF-β signaling

KW - arterial dilatation

KW - connective tissue disorder

KW - joint hyperlaxity

UR - http://www.scopus.com/inward/record.url?scp=85107047438&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2021.04.020

DO - 10.1016/j.ajhg.2021.04.020

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34010604

AN - SCOPUS:85107047438

SN - 0002-9297

VL - 108

SP - 1126

EP - 1137

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 6

ER -

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

Abstract

Funding

Keywords

UN SDGs

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