A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis
Open accessAbstract
Frequently fatal, primary hemophagocytic lymphohistiocytosis (HLH) occurs in infancy resulting from homozygous mutations in NK and CD8 T cell cytolytic pathway genes. Secondary HLH presents after infancy and may be associated with heterozygous mutations in HLH genes. We report two unrelated teenagers with HLH and an identical heterozygous RAB27A mutation (c.259G→C). We explore the contribution of this Rab27A missense (p.A87P) mutation on NK cell cytolytic function by cloning it into a lentiviral expression vector prior to introduction into the human NK-92 cell line. NK cell degranulation (CD107a expression), target cell conjugation, and K562 target cell lysis was compared between mutant– and wild-type–transduced NK-92 cells. Polarization of granzyme B to the immunologic synapse and interaction of mutant Rab27A (p.A87P) with Munc13-4 were explored by confocal microscopy and proximity ligation assay, respectively. Overexpression of the RAB27A mutation had no effect on cell conjugate formation between the NK and target cells but decreased NK cell cytolytic activity and degranulation. Moreover, the mutant Rab27A protein decreased binding to Munc13-4 and delayed granzyme B polarization toward the immunologic synapse. This heterozygous RAB27A mutation blurs the genetic distinction between primary and secondary HLH by contributing to HLH via a partial dominant-negative effect.
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In patients with secondary HLH, viral, autoimmune, or neoplastic disorders trigger cytokine storm, and such patients often have heterozygous polymorphisms in the same genes altered in primary HLH.
“In patients with secondary HLH, viral, autoimmune, or neoplastic disorders trigger cytokine storm, and such patients often have heterozygous polymorphisms in the same genes that are altered in primary HLH.65,74”
From Cytokine storm (2020) · cites this paper as [65]
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- Authors
- Zhang, M., Bracaglia, C., Prencipe, G., Bemrich-Stolz, C. J., Beukelman, T., Dimmitt, R. A., Chatham, W. W., Zhang, K., Li, H., Walter, M. R., De Benedetti, F., Grom, A. A., & Cron, R. Q.
- Affiliations
- University of Alabama at Birmingham (US)
- Bambino Gesù Children's Hospital (IT)
- Division of Pediatric Hematology–Oncology, University of Alabama at Birmingham , Birmingham, AL 35233
- University of Cincinnati (US)
- Divisione di Reumatologia Pediatrica, Ospedale Pediatrico Bambino Gesù , 00165 Rome ,
- Corresponding author
- Zhang, Mingce
- Beukelman, Timothy
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03
- Volume
- 196
- Issue
- 6
- Pages
- 2492-2503
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4779709
- OpenAlex
- W2273582653
- Cited by
- 99
- References
- 52
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 21 · 2023: 5 · 2022: 10 · 2021: 8 · 2020: 12 · 2019: 23 · 2018: 4 · 2017: 7 · 2016: 2
- FWCI
- 11.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI049342, R01AI097629)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059049, P30AR048311)
- Topics
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Keywords
- Rab27a, hemophagocytic lymphohistiocytosis, secondary hemophagocytic lymphohistiocytosis, NK cell cytotoxicity, granzyme B, immunological synapse, Munc13-4, NK cell degranulation, missense mutations, dominant negative effect, lentiviral transduction, NK-92 cells
- MeSH terms
- rab27 GTP-Binding Proteins, Adolescent, Cell Line, Cytoplasmic Granules, Female, Heterozygote, Humans, Killer Cells, Natural, Male, Transduction, Genetic, Cell Degranulation, Microscopy, Confocal, Mutation, Missense, Reverse Transcriptase Polymerase Chain Reaction, rab GTP-Binding Proteins, Immunoprecipitation, Lymphohistiocytosis, Hemophagocytic
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