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
  • 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].
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.