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

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.
Alban Ziegler 1,  Rémi Duclaux-Loras 2,  Céline Revenu 3,  Fabienne Charbit-Henrion 4,  Bernadette Begue 2,  Karine Duroure 3,  Linda Grimaud 5,  Anne Laure Guihot 5,  Valérie Desquiret-Dumas 1,  Mohammed Zarhrate 6,  Nicolas Cagnard 7,  Emmanuel Mas 8,  Anne Breton 8,  Thomas Edouard 9,  Clarisse Billon 10,  Michael Frank 10,  Estelle Colin 11,  Guy Lenaers 5,  Daniel Henrion 5,  Stanislas Lyonnet 12,  Laurence Faivre 13,  Yves Alembik 14,  Anaïs Philippe 14,  Bruno Moulin 15,  Eyal Reinstein 16,  Shay Tzur 17,  Ruben Attali 17,  George McGillivray 18,  Susan M White 18,  Lyndon Gallacher 19,  Kerstin Kutsche 20,  Pauline Schneeberger 20,  Katta M Girisha 21,  Shalini S Nayak 21,  Lynn Pais 22,  Reza Maroofian 23,  Aboulfazl Rad 24,  Barbara Vona 25,  Ehsan Ghayoor Karimiani 26,  Caroline Lekszas 27,  Thomas Haaf 27,  Ludovic Martin 28,  Frank Ruemmele 29,  Dominique Bonneau 1,  Nadine Cerf-Bensussan 2,  Filippo Del Bene 30,  Marianna Parlato 31
Affiliations

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: filippo.del-bene@inserm.fr.
  • 31 Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM, UMR1163, 75015 Paris, France. Electronic address: marianna.parlato@inserm.fr.
PMID: 34010604 DOI: 10.1016/j.ajhg.2021.04.020
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.

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