Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation
Alban Ziegler
(1, 2)
,
Rémi Duclaux-Loras
(3)
,
Céline Revenu
(4)
,
Fabienne Charbit-Henrion
(3)
,
Bernadette Begue
(3)
,
Karine Duroure
(4)
,
Linda Grimaud
(2)
,
Anne Laure Guihot
(2)
,
Valérie Desquiret-Dumas
(1, 2)
,
Mohammed Zarhrate
(5)
,
Nicolas Cagnard
(5)
,
Emmanuel Mas
(6)
,
Anne Breton
(7)
,
Thomas Edouard
(8)
,
Clarisse Billon
(9)
,
Michael Frank
(9)
,
Estelle Colin
(1)
,
Guy Lenaers
(2)
,
Daniel Henrion
(2)
,
Stanislas Lyonnet
(10, 11)
,
Laurence Faivre
(12)
,
Yves Alembik
(13)
,
Anaïs Philippe
(13)
,
Bruno Moulin
(14)
,
Eyal Reinstein
(15)
,
Shay Tzur
(16)
,
Ruben Attali
(16)
,
George Mcgillivray
(17)
,
Susan M White
(17)
,
Lyndon Gallacher
(17)
,
Kerstin Kutsche
(18)
,
Pauline Schneeberger
(18)
,
Katta M Girisha
(19)
,
Shalini S Nayak
(19)
,
Lynn Pais
(20)
,
Reza Maroofian
(21)
,
Aboulfazl Rad
(22)
,
Barbara Vona
(22)
,
Ehsan Ghayoor Karimiani
(23)
,
Caroline Lekszas
(24)
,
Thomas Haaf
(24)
,
Ludovic Martin
(2, 1)
,
Frank Ruemmele
(5, 11)
,
Dominique Bonneau
(1, 2)
,
Nadine Cerf-Bensussan
(3)
,
Filippo del Bene
(4)
,
Marianna Parlato
(3)
1
CHU Angers -
Centre Hospitalier Universitaire d'Angers
2 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
3 Equipe Inserm U1163 - Laboratory of Intestinal Immunity
4 Institut de la Vision
5 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
6 IRSD - Institut de Recherche en Santé Digestive
7 IRSD - Ingénierie Radioprotection Sûreté Démantèlement
8 RESTORE - Geroscience and rejuvenation research center
9 HEGP - Hôpital Européen Georges Pompidou [APHP]
10 Embryology and genetics of human malformation
11 Hôpital Necker - Enfants Malades [AP-HP]
12 FHU TRANSLAD (CHU de Dijon)
13 Hôpital de Hautepierre [Strasbourg]
14 Nouvel Hôpital Civil de Strasbourg
15 TAU - Tel Aviv University
16 Emedgene Technologies [Tel Aviv]
17 MCRI - Murdoch Children's Research Institute
18 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
19 Kasturba Medical College, Manipal
20 MIT - Massachusetts Institute of Technology
21 UCL - University College of London [London]
22 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
23 St George's, University of London
24 JMU - Julius-Maximilians-Universität Würzburg
2 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
3 Equipe Inserm U1163 - Laboratory of Intestinal Immunity
4 Institut de la Vision
5 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
6 IRSD - Institut de Recherche en Santé Digestive
7 IRSD - Ingénierie Radioprotection Sûreté Démantèlement
8 RESTORE - Geroscience and rejuvenation research center
9 HEGP - Hôpital Européen Georges Pompidou [APHP]
10 Embryology and genetics of human malformation
11 Hôpital Necker - Enfants Malades [AP-HP]
12 FHU TRANSLAD (CHU de Dijon)
13 Hôpital de Hautepierre [Strasbourg]
14 Nouvel Hôpital Civil de Strasbourg
15 TAU - Tel Aviv University
16 Emedgene Technologies [Tel Aviv]
17 MCRI - Murdoch Children's Research Institute
18 UKE - Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg]
19 Kasturba Medical College, Manipal
20 MIT - Massachusetts Institute of Technology
21 UCL - University College of London [London]
22 Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen
23 St George's, University of London
24 JMU - Julius-Maximilians-Universität Würzburg
Karine Duroure
- Fonction : Auteur
- PersonId : 775313
- ORCID : 0000-0002-5959-569X
Thomas Edouard
- Fonction : Auteur
- PersonId : 808409
- ORCID : 0000-0002-9222-5009
- IdRef : 066958652
Clarisse Billon
- Fonction : Auteur
- PersonId : 805108
- ORCID : 0000-0002-7104-8496
Michael Frank
- Fonction : Auteur
- PersonId : 760562
- ORCID : 0000-0001-8451-0523
Guy Lenaers
- Fonction : Auteur
- PersonId : 180103
- IdHAL : guy-lenaers
- ORCID : 0000-0003-2736-3349
- IdRef : 109925726
Daniel Henrion
- Fonction : Auteur
- PersonId : 181738
- IdHAL : daniel-henrion-inserm
Laurence Faivre
- Fonction : Auteur
- PersonId : 757929
- ORCID : 0000-0001-9770-444X
Aboulfazl Rad
- Fonction : Auteur
- PersonId : 807164
- ORCID : 0000-0001-8627-8828
Barbara Vona
- Fonction : Auteur
- PersonId : 798052
- ORCID : 0000-0002-6719-3447
Thomas Haaf
- Fonction : Auteur
- PersonId : 786127
- ORCID : 0000-0002-0737-0763
Ludovic Martin
- Fonction : Auteur
- PersonId : 759799
- ORCID : 0000-0002-4325-6765
Filippo del Bene
- Fonction : Auteur
- PersonId : 777258
- ORCID : 0000-0001-8551-2846
- IdRef : 169113949
Résumé
Dysregulated transforming growth factor TGF-beta 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-beta-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-beta 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-beta signaling during development and reinforces the existing link between TGF-beta signaling and connective tissue defects.
Origine : Publication financée par une institution
