Molecular Pathogenesis
The result of biallelic pathogenic variants in PRF1, UNC13D (formerly MUNC13-4), STX11, and STXBP2 is defective perforin-mediated killing of target cells, also known as lymphocyte cytotoxicity [de Saint Basile et al 2010]. Lymphocyte cytotoxicity is important for killing of infected and malignant cells, as well as maintenance of immune homeostasis.
PRF1 encodes perforin, which is predominately expressed by lymphocytes of the CD8+ T-cell and NK-cell lineages [Stepp et al 1999]. Perforin is essential for cell-mediated cytotoxicity. Perforin is stored in specialized secretory lysosomal vesicles commonly termed cytotoxic granules. Besides perforin, cytotoxic granules contain granzymes and other proteins that promote target cell death. Upon recognition of a susceptible target cell, cytotoxic lymphocytes release granule contents toward the target cells in a regulated manner, whereupon perforin subunits rapidly form pores in the target cell membrane that serve as conduits for entry of granzymes into the target cell [Lopez et al 2013]. Granzymes are serine proteases that induce apoptosis (cell death) of the target cells. The process of granzyme-mediated lymphocyte cytotoxicity is important for control of infection, protection against cancer, and downregulation of the immune response. Failure to carry out this process can lead to overactivation of the immune response resulting in the signs and symptoms of familial hemophagocytic lymphohistiocytosis (fHLH).
UNC13D, STX11, and STXBP2 encode the cytoplasmic proteins Munc13-4, syntaxin-11, and Munc18-2, respectively. They are expressed in most hematopoietic cells. Deficiency in any one of these proteins results in defective exocytosis of secretory lysosome contents, a prerequisite for lymphocyte cytotoxicity. Deficiencies in these proteins also result in defective exocytosis from other hematopoietic cells, including platelets, neutrophils, and mast cells. Nonetheless, the phenotypes of individuals harboring biallelic pathogenic variants in UNC13D, STX11, and STXBP2 are largely the same as that associated with pathogenic variants in PRF1.
At the cellular level, syntaxin-11 is a membrane-associated SNARE protein that interacts with other SNARE proteins to drive membrane fusion. Signals from activating receptors recruit syntaxin-11 from recycling endosomes to the plasma membrane in a VAMP-8 dependent manner [Marshall et al 2015]. Munc18-2 regulates syntaxin-11 trafficking and function, whereas Munc13-4 primes vesicle exocytosis, in part by sensing elevated intracellular Ca2+ concentrations required for cytotoxic granule exocytosis [Boswell et al 2012]. Notably, cytokine activation of lymphocytes can bypass a requirement for syntaxin-11 in exocytosis, explaining a typically later onset and somewhat milder course of disease in individuals with syntaxin-11 deficiency [Bryceson et al 2007, Sepulveda et al 2013].
Marsh et al [2010] noted that pathogenic missense variants in STX11 are associated with preserved NK cell function compared to nonsense variants, which resulted in abrogation of NK cell function.
Mechanism of disease causation. The vast majority of fHLH is associated with autosomal recessive loss-of-function pathogenic variants in the four well-described fHLH genes (PRF1, STXBP2, STX11, and UNC13D).
However, two reports provide evidence for three STXBP2 variants with gain of function: p.Arg65Trp, p.Arg65Gln [Spessott et al 2015], and p.Arg190Cys [Benavides et al 2020], which impair lymphocyte cytotoxicity and act in dominant-negative manner. The variants reported by Spessott et al [2015] are associated with late-onset fHLH.
Gene-specific laboratory technical considerations: UNC13D. Two deep intronic variants (c.118-308C>T and c.118-307G>A) and one large gene inversion have been identified as causative of early-onset fHLH [Meeths et al 2011, Entesarian et al 2013].
A large 253-kb inversion straddles the UNC13D 3' end and adjacent sequences, abolishing protein expression; the breakpoints have been mapped and the inversion is detectable by targeted analysis for pathogenic variants (see Table 2).
The deep intronic variants lie within an intron 1 region that is typically not sequenced; detection will require specific primers. The c.118-308C>T and c.118-307G>A variants disrupt a lymphocyte-specific enhancer and alternative transcriptional start site, specifically impairing gene transcription in lymphocytes [Cichocki et al 2014].
The deep intronic (c.117+143A>G) variant disrupts an enhancer and has been associated with reduced gene transcription and macrophage activation in a single individual [Schulert et al 2018].
Table 7.
Familial Hemophagocytic Lymphohistiocytosis: Notable Pathogenic Variants by Gene
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
- 1.
Variant designation that does not conform to current naming conventions