Structure/Function Relationships in the MUNC13-4 Protein: Molecular Consequences of Familial Hemophagocytic Lymphohistiocytosis Associated Mutations
Janos Sumegi MD
Cincinnati Children’s Hospital Medical Center – Cincinnati, Ohio USA
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Hemophagocytic lymphohistiocytosis is a rare life-threatening immune disorder, often referred to as “orphan”, characterized by fever, hepatosplenomegaly, and pancytopenia, hypertriglyceridemia, hypofibrinogenemia and, frequently seizures. HLH has been categorized, clinically as primary or secondary HLH. The primary form, known as familial HLH (FHLH), an autosomal recessive disease invariably fatal when untreated, can result from a variety of pathologic gene mutations that affect critical pathways, which regulate the function of cytotoxic T-cells and NK cells. Genetic defects in NK cell function permit excessive expansion of antigen presenting cells (histiocytes) and T-cells in response to immune activation, and the consequent prolonged secretion of proinflammatory cytokines. The failure of NK cell regulation of activated populations of immune cells results in the clinical manifestations of HLH. Mutations in the MUNC13-4 gene encoding a protein which primes the function of the downstream protein receptors required for exocytosis of the lytic granules. Exocytosis of the lytic granules is a key event in the apoptotic killing of target cells suggesting that the underlying defect in FHLH is the lack of apoptosis triggering within the immune system. This proposal offers: to study the consequences of naturally occurring pathologic mutations of MUNC13-4 on the structure and function of the protein.