Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive disorder characterized by hyperactive phagocytes and defects in natural killer cell function. It has been shown previously that mutations in the perforin 1 gene (PRF1) and in UNC13D are associated with FHL2 and FHL3, respectively, indicating genetic heterogeneity. We performed genome-wide homozygosity mapping in a large consanguineous Kurdish kindred with five children affected with FHL. Linkage to a 10 cM region on chromosome 6q24 between D6S1569 and D6S960 defined a novel FHL locus. By screening positional candidate genes, we identified a homozygous deletion of 5 bp in the syntaxin 11 gene (STX11) in this family. We could demonstrate that syntaxin 11 protein was absent in the mononuclear cell fraction of patients with the homozygous 5 bp deletion. In addition to this family, we found homozygous mutations in STX11 in five consanguineous Turkish/Kurdish FHL kindreds including two families with the 5 bp deletion, one family with a large 19.2 kb genomic deletion spanning the entire coding region of STX11 (exon 2) and two families with a nonsense mutation that leads to a premature stop codon in the C-terminal end of the protein. As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL.

Syntaxin 11 is required for NK and CD8+ T‐cell cytotoxicity and neutrophil degranulation

“…Defective NK cell degranulation and cytotoxicity have been identified in patients with FHL-4, which correlates with a deficiency in STX11 expression [5,13]. Therefore we investigated whether a constitutive deficiency of STX11 in NK cells and CTL results in dysregulated degranulation and granule exocytosis in both cell types and whether this altered effector function correlates with a specific NK or CD8 + T-cell phenotype.…”

“…MUNC13-4 and Rab27a) and STX11 [10][11][12][13]. The underlying pathology is the familial hemophagocytic lymphohistiocytosis (FHL), a rare autosomal recessive disorder characterised by an increased inflammatory response with abnormal secretion of proinflammatory cytokines TNF,.…”

“…This is in concert with previous findings in lymphocytes from healthy donors and FHL type 4 patient samples showing that a deficiency in STX11 leads to an impaired degranulation and cytotoxic activity [4,5]. Thus, Stx11 −/− mice that were found to carry no overt defect in immune system development and immune cell populations in lymphatic tissues could be an ideal in vivo model for further dissecting the Hemophagocytic Lymphohistiocytosis (HLH) pathogenesis, in particular FHL-4 which is caused by a mutated STX11 gene in humans [13]. Nevertheless, Stx11 −/− mice would still represent an important tool for investigating the principles of cytotoxic lymphocyte degranulation and vesicular trafficking.…”

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

“…Although the cytolytic cells of the patients with FHLH caused by MUNC13-4 mutations produce sufficient amounts of perforin, the poor ability to deliver the content of the cytolytic granules to the immunologic synapse with the target cell leads to profoundly decreased cytolytic activity. More recently, mutations in two other genes encoding proteins that facilitate granule fusion in intracellular trafficking events have been linked to the development of primary HLH: Syntaxin 11, a member of the SNARE protein family, 28 and syntaxin binding protein 2 (STXBP2, also known as MUNC18-2) 27 ( Figure 2).…”

“…48 Munc13-4 is likely important in activating Syntaxin 11 that in turn is important for vesicle fusion. 25,28 Absence of any these molecules prevents the release of perforin and therefore destruction of target antigenpresenting cells (Figure 2). Accordingly, mice deficient in the genes encoding Munc13-4 49 and Rab27a 50,51 also develop HLH upon infection with lymphochoriomeningitic virus in an IFNgdependent manner.…”