A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13‐4 function

  title={A novel Dutch mutation in UNC13D reveals an essential role of the C2B domain in munc13‐4 function},
  author={Edo D Elstak and Maroeska Te Loo and Kiki Tesselaar and Peter van Kerkhof and Jan L Loeffen and Dimitris Grivas and Eric Fam Hennekam and Jaap Jan Boelens and Peter M Hoogerbrugge and Peter van der Sluijs and Marielle van Gijn and Lisette van de Corput},
  journal={Pediatric Blood \& Cancer},
UNC13D, encoding the protein munc13‐4, is essential in intracellular trafficking and exocytosis of lytic granules. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a genetically heterogeneous, rare autosomal recessive immune disorder. How mutations affect function of munc13‐4 is poorly understood. Since 2006 we genetically identified seven FHL patients with mutations in UNC13D. 
Lentiviral gene therapy for familial hemophagocytic lymphohistiocytosis type 3, caused by UNC13D genetic defects.
An optimized lentiviral vector is described that can restore Munc13-4 expression and degranulation capacity in both transduced FHL3 patient T cells as well as transducing hematopoietic stem cells from the FHL2 (Jinx) disease model.
Munc 13 ‐ 4 mediates human neutrophil elastase ‐ induced airway mucin 5 AC hypersecretion by interacting with syntaxin 2
The results of the present study indicate that Munc13‐2 may be an essential regulator of basal MUC5AC exocytosis, while Munc 13‐4 appears to be a Munc14 protein subtype that may to be sensitive to hNE stimulation during airway Muc5AC hypersecretion.
UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion
It is shown that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation, suggesting that UNC- 45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.
Altered gene expression and possible immunodeficiency in cases of sudden infant death syndrome
It is indicated that there is an altered expression of genes involved in the inflammatory process in a proportion of SIDS cases, which further strengthen the hypothesis that impaired immune response play a role in this syndrome.
Late Steps in Secretory Lysosome Exocytosis in Cytotoxic Lymphocytes
This minireview highlights recent progress in knowledge of late steps in this specialized secretion pathway and addresses important open questions in Natural Killer cells.


A platform for complementation and characterization of familial haemophagocytic lymphohistiocytosis 3 mutations.
Aberrant maturation of mutant perforin underlies the clinical diversity of hemophagocytic lymphohistiocytosis.
It is shown, for the first time to the knowledge, that recombinant human perforin is expressed, processed appropriately, and functional in rat basophilic leukemia (RBL) cells following retroviral transduction.
Munc13-4 is an effector of rab27a and controls secretion of lysosomes in hematopoietic cells.
It is proposed that the secretion defects seen in GS2 and FHL3 have a common origin, and it is suggested that the rab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells.
Functional assessment of perforin C2 domain mutations illustrates the critical role for calcium-dependent lipid binding in perforin cytotoxic function.
This study clearly demonstrates the pathogenicity of the T435M mutation and illustrates, for the first time, the critical role of the human perforin C2 domain for calcium-dependent, cytotoxic function.
Perforin-mediated target-cell death and immune homeostasis
Recent progress is described in defining the structure, function, biochemistry and cell biology of perforin.
Inherited defects in lymphocyte cytotoxic activity
Analysis of the mechanisms leading to the occurrence of hemophagocytic syndrome designates γ‐interferon as an attractive therapeutic target to downregulate uncontrolled macrophage activation, which sustains clinical and biological features of HLH.
Munc13-4 Regulates Granule Secretion in Human Neutrophils1
It is shown that Munc13-4 is expressed in human neutrophils, and that its expression is increased during granulocytic differentiation of HL-60 and PLB-985 cells, and this findings suggest a role for Munc 13-4 as a component of the secretory machinery in neutrophil.
Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes.
Interactions of the MUN domain of Munc13-1, key for this priming function, are analyzed, and it is suggested that unc13/Munc13s may provide a template to assemble syntaxin-1/SNAP-25 heterodimers, leading to an acceptor complex for synaptobrevin.
Molecular Dynamics of a Presynaptic Active Zone Protein Studied in Munc13-1–Enhanced Yellow Fluorescent Protein Knock-In Mutant Mice
Evidence is provided that presynaptic active zones of mammalian CNS synapses are highly dynamic structures and the usefulness of the knock- in approach in general and of Munc13-1–EYFP knock-in mice in particular for imaging synaptic protein dynamics is demonstrated.