PUBLICATION
NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation
- Authors
- Castro, C.N., Rosenzwajg, M., Carapito, R., Shahrooei, M., Konantz, M., Khan, A., Miao, Z., Groß, M., Tranchant, T., Radosavljevic, M., Paul, N., Stemmelen, T., Pitoiset, F., Hirschler, A., Nespola, B., Molitor, A., Rolli, V., Pichot, A., Faletti, L.E., Rinaldi, B., Friant, S., Mednikov, M., Karauzum, H., Aman, M.J., Carapito, C., Lengerke, C., Ziaee, V., Eyaid, W., Ehl, S., Alroqi, F., Parvaneh, N., Bahram, S.
- ID
- ZDB-PUB-200810-27
- Date
- 2020
- Source
- The Journal of experimental medicine 217(12): (Journal)
- Registered Authors
- Konantz, Martina, Lengerke, Claudia
- Keywords
- none
- MeSH Terms
-
- Actins/metabolism
- Animals
- Cell Degranulation
- Cell Proliferation
- Child
- Cytotoxicity, Immunologic
- Family
- Female
- Homozygote
- Humans
- Immunologic Deficiency Syndromes/complications*
- Immunologic Deficiency Syndromes/immunology
- Immunological Synapses/metabolism
- Infant
- Inflammation/complications*
- Inflammation/immunology
- Inflammation/pathology
- Lymphocyte Activation/immunology
- Lymphoproliferative Disorders/complications*
- Lymphoproliferative Disorders/immunology
- Male
- Membrane Proteins/chemistry
- Membrane Proteins/deficiency
- Membrane Proteins/genetics
- Membrane Proteins/metabolism*
- Mutation/genetics
- Pedigree
- Phenotype
- Syndrome
- Zebrafish
- PubMed
- 32766723 Full text @ J. Exp. Med.
Citation
Castro, C.N., Rosenzwajg, M., Carapito, R., Shahrooei, M., Konantz, M., Khan, A., Miao, Z., Groß, M., Tranchant, T., Radosavljevic, M., Paul, N., Stemmelen, T., Pitoiset, F., Hirschler, A., Nespola, B., Molitor, A., Rolli, V., Pichot, A., Faletti, L.E., Rinaldi, B., Friant, S., Mednikov, M., Karauzum, H., Aman, M.J., Carapito, C., Lengerke, C., Ziaee, V., Eyaid, W., Ehl, S., Alroqi, F., Parvaneh, N., Bahram, S. (2020) NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation, and hyperinflammation. The Journal of experimental medicine. 217(12):.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping