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

Am J Hum Genet. 2021 Jun 3;108(6):1126-1137. doi: 10.1016/j.ajhg.2021.04.020. Epub 2021 May 18.

Authors

Alban Ziegler¹, Rémi Duclaux-Loras², Céline Revenu³, Fabienne Charbit-Henrion⁴, Bernadette Begue², Karine Duroure³, Linda Grimaud⁵, Anne Laure Guihot⁵, Valérie Desquiret-Dumas¹, Mohammed Zarhrate⁶, Nicolas Cagnard⁷, Emmanuel Mas⁸, Anne Breton⁸, Thomas Edouard⁹, Clarisse Billon¹⁰, Michael Frank¹⁰, Estelle Colin¹¹, Guy Lenaers⁵, Daniel Henrion⁵, Stanislas Lyonnet¹², Laurence Faivre¹³, Yves Alembik¹⁴, Anaïs Philippe¹⁴, Bruno Moulin¹⁵, Eyal Reinstein¹⁶, Shay Tzur¹⁷, Ruben Attali¹⁷, George McGillivray¹⁸, Susan M White¹⁸, Lyndon Gallacher¹⁹, Kerstin Kutsche²⁰, Pauline Schneeberger²⁰, Katta M Girisha²¹, Shalini S Nayak²¹, Lynn Pais²², Reza Maroofian²³, Aboulfazl Rad²⁴, Barbara Vona²⁵, Ehsan Ghayoor Karimiani²⁶, Caroline Lekszas²⁷, Thomas Haaf²⁷, Ludovic Martin²⁸, Frank Ruemmele²⁹, Dominique Bonneau¹, Nadine Cerf-Bensussan², Filippo Del Bene³⁰, Marianna Parlato³¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, CHU d'Angers, 49000 Angers, France; University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France.
² Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France.
³ Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75005 Paris, France.
⁴ Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France; Department of Pediatric Gastroenterology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France; Department of Molecular Genetics, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
⁵ University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France.
⁶ Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163 et INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cité University, 75015 Paris, France.
⁷ Bioinformatics Core Facility, INSERM-UMR 1163, Imagine Institute, 75015 Paris, France.
⁸ IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse 31300, France; Centre de Référence des Maladies Rares Digestives, and Pediatric Clinical Research Unit, Toulouse Clinical Investigation Center INSERM U1436, Hôpital des Enfants, CHU de Toulouse, Toulouse 31300, France.
⁹ Reference Centre for Marfan Syndrome and Reference Centre on Rare Bone Diseases, Pediatric Clinical Research Unit, Children's Hospital, Toulouse University Hospital, RESTORE, INSERM UMR1301, 31300 Toulouse, France.
¹⁰ Centre de Génétique, Centre de Référence des Maladies Vasculaires Rares, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75015 Paris, France.
¹¹ Department of Biochemistry and Molecular Biology, CHU d'Angers, 49000 Angers, France.
¹² Université de Paris, Imagine Institute, Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, 75015 Paris, France; Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, 75015 Paris, France.
¹³ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon, 21000 Dijon, France.
¹⁴ Département de Génétique Médicale, CHU de Hautepierre, 67200 Strasbourg, France.
¹⁵ Nephrology and Transplantation Department, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France.
¹⁶ Medical Genetics Institute, Meir Medical Center, Kfar-Saba 4428164, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
¹⁷ Genomic Research Department, Emedgene Technologies, 67443 Tel Aviv, Israel.
¹⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Melbourne, VIC, Australia.
¹⁹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville 3052, Melbourne, VIC, Australia; Department of Paediatrics, The University of Melbourne, 3010 Parkville, Melbourne, VIC, Australia.
²⁰ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
²¹ Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India.
²² Broad Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
²³ Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, WC1N 3BG London, UK.
²⁴ Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany.
²⁵ Department of Otolaryngology-Head & Neck Surgery, Tübingen Hearing Research Centre, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany; Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.
²⁶ Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace London, SW17 ORE London, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azdad University, Mashhad 9133736351, Iran.
²⁷ Institute of Human Genetics, Julius Maximilians University Würzburg, 97074 Würzburg, Germany.
²⁸ University of Angers, MitoVasc, UMR CNRS 6015, INSERM 1083, 49933 Angers, France; Department of Dermatology, CHU d'Angers, 49000 Angers, France.
²⁹ Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France; Department of Pediatric Gastroenterology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, 75015 Paris, France.
³⁰ Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 Rue Moreau, 75012 Paris, France; Institut Curie, PSL Research University, INSERM U934, CNRS UMR3215, 75005 Paris, France. Electronic address: [email protected].
³¹ Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France. Electronic address: [email protected].

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.

Publication types

Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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

Substances

IPO8 protein, human
Transforming Growth Factor beta
beta Karyopherins

Abstract

Publication types

MeSH terms

Substances

Grants and funding