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New Genetic Cause Of A Fatal Immune Disorder

November 3, 2009

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, Genevive 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.

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