An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2

• Published in: Frontiers in immunology Vol. 4; p. 515
• Main Authors: Müller, Martha-Lena, Chiang, Samuel C C, Meeths, Marie, Tesi, Bianca, Entesarian, Miriam, Nilsson, Daniel, Wood, Stephanie M, Nordenskjöld, Magnus, Henter, Jan-Inge, Naqvi, Ahmed, Bryceson, Yenan T
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2014
• Subjects: cytotoxic T lymphocyte (CTL); degranulation; hemopagocytic lymphohistocytosis; Immunology; Medicin och hälsovetenskap; NK cells; Primary Immunodeficiency Diseases; N-peptide; familial hemophagocytic lymphohistiocytosis; syntaxin-11; Munc18-2
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2013.00515

Familial hemophagocytic lymphohistiocytosis (FHL) is an often-fatal hyperinflammatory disorder caused by autosomal recessive mutations in PRF1, UNC13D, STX11, and STXBP2. We identified a homozygous STX11 mutation, c.173T > C (p.L58P), in three patients presenting clinically with hemophagocytic lymphohistiocytosis from unrelated Pakistani families. The mutation yields an amino acid substitution in the N-terminal Habc domain of syntaxin-11 and resulted in defective natural killer cell degranulation. Notably, syntaxin-11 expression was decreased in patient cells. However, in an ectopic expression system, syntaxin-11 L58P was expressed at levels comparable to wild-type syntaxin-11, but did not bind Munc18-2. Moreover, another N-terminal syntaxin-11 mutant, R4A, also did not bind Munc18-2. Thus, we have identified a novel missense STX11 mutation causative of FHL type 4. The syntaxin-11 R4A and L58P mutations reveal that both the N-terminus and Habc domain of syntaxin-11 are required for binding to Munc18-2, implying similarity to the dynamic binary binding of neuronal syntaxin-1 to Munc18-1.