Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, fatal, immune disorder characterized by uncontrolled activation of immune cells known as lymphocytes and macrophages. Disease-causing mutations have been identified in several genes that generate proteins involved in lymphocyte-mediated cell death, including syntaxin-11. Now, Geneviève de Saint Basile and colleagues, at INSERM U768, France, have added a new gene to this list by determining that two distinct mutations in the gene that generates syntaxin-binding protein 2 (Munc18-2; also known as STXBP2) cause disease in a subset of patients with FHL; this form of the disease was then termed 'FHL5'.
Mechanistically, the two distinct STXBP2 mutations led to substantially decreased STXBP2 protein in patient lymphoblasts and impaired release of death-inducing molecules from immune cells known as NK cells. Further analysis indicated that the predominant protein to which STXBP2 binds in lymphocytes is syntaxin-11. The authors therefore conclude that STXBP2 binds syntaxin-11, thereby controlling a late step of the secretory pathway that releases death-inducing molecules; in patients with FHL5, the STXBP2 protein deficiency means this process cannot occur efficiently.
TITLE: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells
AUTHOR CONTACT:
Geneviève de Saint Basile
INSERM U768, Hôpital Necker, Paris, France.
Phone: 33-1-44-49-50-80; Fax: 33-1-42-73-06-40; E-mail: genevieve.de-saint-basile@inserm.fr .
View this article at: http://www.jci.org/articles/view/40732?key=HIH915i5gkk549w2m55m
Journal of Clinical Investigation