A heterozygous RAB27A mutation associated with delayed cytolytic granule polarization and hemophagocytic lymphohistiocytosis

Mingce Zhang, Claudia Bracaglia, Giusi Prencipe, Christina J. Bemrich-Stolz, Timothy Beukelman, Reed A. Dimmitt, W. Winn Chatham, Kejian Zhang, Hao Li, Mark R. Walter, Fabrizio De Benedetti, Alexei A. Grom, Randy Q. Cron

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)2492-2503
Number of pages12
JournalJournal of Immunology
Issue number6
Publication statusPublished - Mar 15 2016

ASJC Scopus subject areas

  • Immunology


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