Case Report: Characterizing the Role of the STXBP2-R190C Monoallelic Mutation Found in a Patient With Hemophagocytic Syndrome and Langerhans Cell Histiocytosis

Laura Viñas-Giménez,Xavier De La Cruz,Mónica Martínez-Gallo,Laia Alsina,Rafael Rincón,Roger Colobran,José Luis Dapena,Joan Sayós,Verónica Paola Celis

doi:10.3389/fimmu.2021.723836

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disorder. HLH can be considered as a threshold disease depending on the trigger and the residual NK-cell cytotoxicity. In this study, we analyzed the molecular and functional impact of a novel monoallelic mutation found in a patient with two episodes of HLH. A 9-month-old child was diagnosed at 2 months of age with cutaneous Langerhans cell histiocytosis (LCH). After successful treatment, the patient developed an HLH episode. At 16 month of age, the patient went through an HSCT losing the engraftment 5 months later concomitant with an HLH relapse. The genetic study revealed a monoallelic mutation in the STXBP2 gene (.pArg190Cys). We transfected COS7 cells to analyze the STXBP2-R190C expression and to test the interaction with STX11. We used the RBL-2H3 cell line expressing STXBP2-WT-EGFP or R190C-EGFP for degranulation assays. Mutation STXBP2-R190C did not affect protein expression or interaction with syntaxin-11. However, we have demonstrated that STXBP2-R190C mutation diminishes degranulation in the RBL-2H3 cell line compared with the RBL-2H3 cell line transfected with STXBP2-WT or nontransfected. These results suggest that STXBP2-R190C mutation acts as a modifier of the degranulation process producing a decrease in degranulation. Therefore, under homeostatic conditions, the presence of one copy of STXBP2-R190 could generate sufficient degranulation capacity. However, it is likely that early in life when adaptive immune system functions are not sufficiently developed, an infection may not be resolved with this genetic background, leading to a hyperinflammation syndrome and eventually develop HLH. This analysis highlights the need for functional testing of new mutations to validate their role in genetic susceptibility and to establish the best possible treatment for these patients.

Highlights

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem hyperinflammatory syndrome characterized by persistent macrophages/lymphocytes activation
To study the pathologic role of this mutation and the ability to interact with STX11, the COS-7 cell line was transiently cotransfected with the HA-STXBP2-R190C and GFP-STX11-WT
Co-immunoprecipitation experiments of HA-STXBP2-WT with GFP-STX11-WT showed a band at 66 kDa when using the anti-STXBP2 antibody, indicating a normal interaction between proteins demonstrating that STXBP2R190C maintains the ability to interact with STX11 (Figure 1D)

Summary

INTRODUCTION

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem hyperinflammatory syndrome characterized by persistent macrophages/lymphocytes activation. The term “sporadic HLH” has been applied to patients in whom, in spite of a high level of clinical suspicion, the currently available tests did not detect functional abnormalities [4]. In most of these cases, the age of onset of disease is delayed, and the severity of the symptoms is reduced comparing with traditional FHL. We describe a 9-month-old boy, born from nonconsanguineous parents, with past medical history of cutaneous Langerhans cell histiocytosis (LCH) diagnosed at 2 months of age He was admitted to our institution with an exacerbation of cutaneous lesions, fever, vomit, hypoalbuminemia, diarrhea, and generalized edema; an extended study of the disease is performed confirming the diagnosis of systemic LCH. We performed a careful clinical and molecular evaluation of the patient providing additional arguments for the STXBP2-R190C pathogenicity

METHODS

RESULTS AND DISCUSSION

ETHICS STATEMENT