ArticleJournal of immunology (Baltimore, Md. : 1950)2016
A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis.
Article in Journal of immunology (Baltimore, Md. : 1950), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 97 citations in OpenAlex.
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- Clinical and genetic analysis of macrophage activation syndrome complicating juvenile idiopathic inflammatory myopathies.Pediatric research · 2025Article
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- Cytokine Storm Syndrome Associated with Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
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- Immunology of Cytokine Storm Syndromes: Natural Killer Cells.Advances in experimental medicine and biology · 2024Review
- Genetics of Primary Hemophagocytic Lymphohistiocytosis.Advances in experimental medicine and biology · 2024Review
- Salvage Therapy and Allogeneic Hematopoietic Cell Transplantation for the Severe Cytokine Storm Syndrome of Hemophagocytic Lymphohistiocytosis.Advances in experimental medicine and biology · 2024Review
- Monocytic Phagocytes in the Immunopathogenesis of Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
Abstract
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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