%A Muller,Martha-Lena %A Meeths,Marie %A Chiang,Samuel %A Tesi,Bianca %A Entesarian,Miriam %A Nilsson,Daniel %A Wood,Stephanie %A Nordenskjöld,Magnus %A Henter,Jan-Inge %A Naqvi,Ahmed %A Bryceson,Yenan %D 2014 %J Frontiers in Immunology %C %F %G English %K hemopagocytic lymphohistocytosis,NK cells,cytotoxic T lymphocyte (CTL),degranulation,Primary Immunodeficiency Diseases %Q %R 10.3389/fimmu.2013.00515 %W %L %M %P %7 %8 2014-January-14 %9 Original Research %+ Dr Yenan Bryceson,Karolinska Institutet,Department of Medicine,Stockholm,S-14186,Sweden,yenan.bryceson@ki.se %# %! N-terminal binding of syntaxin-11 to Munc18-2 %* %< %T An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2 %U https://www.frontiersin.org/articles/10.3389/fimmu.2013.00515 %V 4 %0 JOURNAL ARTICLE %@ 1664-3224 %X 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.