MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity

Blood Advances - Tập 7 - Trang 1531-1535 - 2023
Kerstin Schütze1,2,3, Miriam Groß4,5, Kerstin Cornils1,3, Katharina Wustrau1, Sonja Schneppenheim6, Henning Lenhartz7, G. Christoph Korenke8, Gritta Janka1, Svea Ledig1, Ingo Müller1,3, Stephan Ehl4, Kai Lehmberg1
1Division of Pediatric Stem Cell Transplantation and Immunology in the Department of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany
2Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
3Children’s Cancer Research Institute Hamburg, Hamburg, Germany
4Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
5Faculty of Biology, University of Freiburg, Freiburg, Germany
6Medilys Laborgesellschaft mbH, Hamburg, Germany
7Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany
8Department of Neuropediatrics, University Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany

Tóm tắt

Abstract Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype.

Tài liệu tham khảo

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Blood Advances

Tập 7

1531-1535

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