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Nckap1l Defects Lead to a Novel Syndrome Combining Immunodeficiency, Lymphoproliferation, and Hyperinflammation Publisher Pubmed



Castro CN1 ; Rosenzwajg M1, 2 ; Carapito R5, 6 ; Shahrooei M7, 8 ; Konantz M9 ; Khan A10, 11, 12 ; Miao Z13, 14 ; Gro M1 ; Tranchant T5 ; Radosavljevic M5, 6 ; Paul N5 ; Stemmelen T5 ; Pitoiset F2 ; Hirschler A15 Show All Authors
Authors
  1. Castro CN1
  2. Rosenzwajg M1, 2
  3. Carapito R5, 6
  4. Shahrooei M7, 8
  5. Konantz M9
  6. Khan A10, 11, 12
  7. Miao Z13, 14
  8. Gro M1
  9. Tranchant T5
  10. Radosavljevic M5, 6
  11. Paul N5
  12. Stemmelen T5
  13. Pitoiset F2
  14. Hirschler A15
  15. Nespola B6
  16. Molitor A5
  17. Rolli V5, 6
  18. Pichot A5
  19. Faletti LE1, 16
  20. Rinaldi B17
  21. Friant S17
  22. Mednikov M18
  23. Karauzum H18
  24. Aman MJ18
  25. Carapito C15
  26. Lengerke C9
  27. Ziaee V19, 20
  28. Eyaid W10, 11, 12
  29. Ehl S1, 16
  30. Alroqi F10, 11, 12
  31. Parvaneh N21, 22
  32. Bahram S5, 6
Show Affiliations
Authors Affiliations
  1. 1. Center for Chronic Immunodeficiency, Institute for Immunodeficiency, University of Freiburg, Freiburg, Germany
  2. 2. Biotherapy (Ctr. d'Invest. Clin. Integre en Biotherapies and Immunol.
  3. 3. CIC-BTi) and Inflammation-Immunopathology-Biotherapy Dept. (I2B), Pitie-Salpetriere Hospital, Assistance Publique-Hopitaux de Paris, Paris, France
  4. 4. Institut National de la Sante et de la Recherche Medicale UMR-S 959, Sorbonne Universite, Immunology-Immunopathology-Immunotherapy (i3), Paris, France
  5. 5. Laboratoire d'Immunorhumatologie Moleculaire, Universite de Strasbourg, Federation Hospitalo-Universitaire Omicare, Plateforme Genomax, Federation de Medecine Translationnelle de Strasbourg, Strasbourg, France
  6. 6. Service d'Immunologie Biologique, Plateau Technique de Biologie, Pole de Biologie, Nouvel Hopital Civil, Hopitaux Universitaires de Strasbourg, Strasbourg, France
  7. 7. Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran
  8. 8. Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium
  9. 9. Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland
  10. 10. Department of Pediatrics, King Abdullah Specialized Children's Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia
  11. 11. King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  12. 12. King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
  13. 13. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
  14. 14. Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai, Hongkou, China
  15. 15. Laboratoire de Spectrometrie de Masse Bio-Organique, Institut Pluridisciplinaire Hubert Curien, Universite de Strasbourg, UMR 7178, Strasbourg, France
  16. 16. Department of Pediatrics and AdolescentMedicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  17. 17. Laboratoire de Genetique Moleculaire, Centre National de la Recherche Scientifique, Genomique, Microbiologie, UMR7156/Universite de Strasbourg, Strasbourg, France
  18. 18. Integrated BioTherapeutics, Inc., Rockville, MD, United States
  19. 19. Pediatric Rheumatology Research Group, Tehran University of Medical Sciences, Tehran, Iran
  20. 20. Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
  21. 21. Department of Pediatrics, Division of Allergy and Clinical Immunology, Tehran University of Medical Sciences, Tehran, Iran
  22. 22. Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Experimental Medicine Published:2020


Abstract

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies. © 2020 Rockefeller University Press. All rights reserved.
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