NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation.
Actins
/ metabolism
Animals
Cell Degranulation
Cell Proliferation
Child
Cytotoxicity, Immunologic
Family
Female
Homozygote
Humans
Immunologic Deficiency Syndromes
/ complications
Immunological Synapses
/ metabolism
Infant
Inflammation
/ complications
Lymphocyte Activation
/ immunology
Lymphoproliferative Disorders
/ complications
Male
Membrane Proteins
/ chemistry
Mutation
/ genetics
Pedigree
Phenotype
Syndrome
Zebrafish
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
07 12 2020
07 12 2020
Historique:
received:
03
12
2019
revised:
22
06
2020
accepted:
21
07
2020
entrez:
9
8
2020
pubmed:
9
8
2020
medline:
12
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32766723
pii: 152004
doi: 10.1084/jem.20192275
pmc: PMC7526481
pii:
doi:
Substances chimiques
Actins
0
Membrane Proteins
0
NCKAP1L protein, human
144351-15-5
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108437/Z/15/Z
Pays : United Kingdom
Informations de copyright
© 2020 Castro et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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