ArticleThe Journal of experimental medicine2020
NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation.
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Article in The Journal of experimental medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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52 citing papers in PubMed, 1 synthesis or guideline pooled it, 83 citations in OpenAlex.
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Authors and funding
32 authors at 11 institutions in 9 countries.
Carla Noemi CastroInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Michelle RosenzwajgAssistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Biotherapy (Centre d'Investigation Clinique intégré en Biothérapies & immunologie; CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (i2B), Paris, France.
Raphael CarapitoLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Mohammad ShahrooeiSpecialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
Martina KonantzUniversity of Basel and University Hospital Basel, Department of Biomedicine, Basel, Switzerland.
Amjad KhanDepartment of Pediatrics, King Abdulaziz Medical City, King Abdullah Specialized Children's Hospital, Riyadh, Saudi Arabia.
Zhichao MiaoEuropean Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Miriam GroßInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Thibaud TranchantLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Mirjana RadosavljevicLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Nicodème PaulLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Tristan StemmelenLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Fabien PitoisetAssistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Biotherapy (Centre d'Investigation Clinique intégré en Biothérapies & immunologie; CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (i2B), Paris, France.
Aurélie HirschlerLaboratoire de Spectrométrie de Masse Bio-Organique, Institut Pluridisciplinaire Hubert Curien, UMR 7178, Université de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France.
Benoit NespolaService d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Anne MolitorLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Véronique RolliLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Angélique PichotLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Laura Eva FalettiInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Bruno RinaldiLaboratoire de Génétique Moléculaire, Génomique, Microbiologie, UMR7156/Université de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France.
Sylvie FriantLaboratoire de Génétique Moléculaire, Génomique, Microbiologie, UMR7156/Université de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France.
Mark MednikovIntegrated BioTherapeutics, Inc., Rockville, MD.
Hatice KarauzumIntegrated BioTherapeutics, Inc., Rockville, MD.
M Javad AmanIntegrated BioTherapeutics, Inc., Rockville, MD.
Christine CarapitoLaboratoire de Spectrométrie de Masse Bio-Organique, Institut Pluridisciplinaire Hubert Curien, UMR 7178, Université de Strasbourg, Centre National de la Recherche Scientifique, Strasbourg, France.
Claudia LengerkeUniversity of Basel and University Hospital Basel, Department of Biomedicine, Basel, Switzerland.
Vahid ZiaeePediatric Rheumatology Research Group, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Wafaa EyaidDepartment of Pediatrics, King Abdulaziz Medical City, King Abdullah Specialized Children's Hospital, Riyadh, Saudi Arabia.
Stephan EhlInstitute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Fayhan AlroqiDepartment of Pediatrics, King Abdulaziz Medical City, King Abdullah Specialized Children's Hospital, Riyadh, Saudi Arabia.
Nima ParvanehDivision of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
Seiamak BahramLaboratoire d'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, Institut National de la Santé et de la Recherche Médicale UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg, Laboratory of Excellence TRANSPLANTEX, Université de Strasbourg, Strasbourg, France.
Inserm · FRUniversity of Freiburg · DEIntegrated BioTherapeutics (United States) · USKing Saud bin Abdulaziz University for Health Sciences · SACentre National de la Recherche Scientifique · FRGénétique Moléculaire Génomique Microbiologie · FRTehran University of Medical Sciences · IRUniversity of Basel · CHHôpitaux Universitaires de Strasbourg · FRSina Hospital · IRTongji University · CN
Funding
Wellcome TrustWellcome Trust 108437/Z/15/Z
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.
Indexed as
ActinsAnimalsCell DegranulationCell ProliferationChildCytotoxicity, ImmunologicFamilyFemaleHomozygoteHumansImmunological SynapsesImmunologic Deficiency SyndromesInfantInflammationLymphocyte ActivationLymphoproliferative DisordersActinsMembrane ProteinsNCKAP1L protein, human
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